Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders

ABSTRACT

Provided are compounds of the formula (I): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, tautomer, salt, hydrate or prodrug thereof that modulate tyrosine kinase activity, compositions comprising the compounds and methods of their use.

1. FIELD

Provided are compounds that modulate tyrosine kinase activity,compositions that comprise the compounds and methods of using thecompounds for the treatment or prevention of diseases or conditions thatare characterized by tyrosine kinase activity or expression.

2. BACKGROUND

According to the latest American Cancer Society's annual statisticalreport, released in January 2005, cancer has edged out heart disease asthe leading cause of death in Americans under age 85. In 2002, the mostrecent year for which information is available, 476,009 Americans under85 died of cancer compared with 450,637 who died of heart disease (thoseunder 85 comprise 98.4 percent of the US population). Protein tyrosinekinases (PTK), which historically represented the majority of firstdiscovered oncogenes, remain today one of the most important classes ofoncology drug targets.

Protein kinases are enzymes which covalently modify proteins andpeptides by the attachment of a phosphate group to one or more sites onthe protein or peptide (for example, PTK phosphorylate tyrosine groups).The measurement of protein kinase activity is important since studieshave shown that these enzymes are key regulators of many cell functions.

Over 500 protein kinases have been identified in the human genome(“kinome”) (Manning et al. (2002) Science. 298:1912). Based on therecent advances in deciphering the human genome, the family of human PTKconsists of approximately 90 members (Blume-Jensen and Hunter (2001)Nature, 411: 355-365; Robinson et al. (2000) Oncogene 19:5548-5557).This family can be divided in two major groups—receptor tyrosine kinases(RTK) and cytoplasmic (or non-receptor) tyrosine kinases (CTK)—andapproximately 30 subfamilies based on structural similarity (see, e.g.,Bolen et al. (1992) FASEB J. 6:3403-3409 (1992); Ullrich andSchlessinger (1990) Cell 61:203-212; Ihle (1995) Sem. Immunol.7:247-254. PTKs are involved in regulation of many cellular processes,such as cell proliferation, survival and apoptosis. Enhanced activity ofPTKs has been implicated in a variety of malignant and nonmalignantproliferative diseases. In addition, PTKs play a central role in theregulation of cells of the immune system. PTK inhibitors can thus impacta wide variety of oncologic and immunologic disorders. Such disordersmay be ameliorated by selective inhibition of a certain receptor ornon-receptor PTK, such as LCK, or due to the homology among PTK classes,by inhibition of more than one PTK by an inhibitor.

In some forms of cancer, a PTK mutation or structural alteration canincrease the ability to proliferate, and thus, provides an advantageover surrounding cells. PTK of growth factor receptors, for instance,have been shown to be involved in the transformation of normal tocancerous cells (see, e.g., Rao (1996) Curr. Opin. Oncol. 8:516-524).PTK also play a role in the regulation of apoptosis or programmed celldeath (see, e.g., Anderson (1997) Microbiol. Rev. 61:33). By activationof PTK, apoptosis mechanisms can be shut off and the elimination ofcancerous cells is prevented. Thus, PTK exert their oncogenic effectsvia a number of mechanisms such as driving proliferation and cellmotility and invasion. These PTK include HER2, BCR-ABL, SRC, and IGF1R.

There are many ways that a PTK can become oncogenic. For example,mutations (such as gain-of-function mutations) or small deletions in RTKand/or CTK are known to be associated with several malignancies (e.g.,KIT/SCFR, EGFR/ERBB1, CSF-1R, FGFR1, FGFR3, HGFR, RET). Additionally,overexpression of certain types of PTK resulting, for example, from geneamplification has been shown to be associated with several commoncancers in humans (e.g., EGFR/ERBB1, ERBB2/HER2/NEU, ERBB3/HER3,ERBB4/HER4, CSF-1R, PDGFR, FLK2/FLT3, FLT4NVEGFR3, FGFR1, FGFR2/K-SAM,FGFR4, HGFR, RON, EPHA2, PEHB2, EPHB4, AXL, TIE/TIE1). For a review ofoncogenic kinase signaling, and mutated kinase genes that may be used inthe systems and methods provided herein, see Blume-Jensen and Hunter(2001) Nature 411:355; Tibes et al (2005) Annu. Rev. Pharmacol. Toxicol.45:357; Gschwind (2004) Nature Reviews 4:361; Paul and Mukhopadhay(2004) Int. J. Med. Sci (2004) 1:101.

The majority of PTKs are believed to be important drug targets,especially for anti-cancer therapy. Indeed, a very large proportion ofknown PTKs have been shown to be hyperactivated in cancer cells due tooverexpression or constitutively activating mutations and to directlydrive tumor growth. In addition, a subset of RTKs, such as vascularendothelial growth factor receptors (VEGFR), fibroblast growth factorreceptors (FGFR) and some ephrin receptor (EPH) family members, isinvolved in driving angiogenesis while others (e.g., Met and discoidindomain receptor (DDR)) promote cell motility and invasion (e.g.,metastasis).

The formation of new blood vessels, either from differentiatingendothelial cells during embryonic development (vasculogenesis) or frompre-existing vessels during adult life (angiogenesis), is an essentialfeature of organ development, reproduction, and wound healing in higherorganisms. Folkman and Shing, J. Biol. Chem., 267: 10931-10934 (1992);Reynolds et al., FASEB J., 6: 886-892 (1992); Risau et al., Development,102: 471-478 (1988). Angiogenesis is implicated in the pathogenesis of avariety of disorders, including, but not limited to, solid tumors,intraocular neovascular syndromes such as proliferative retinopathies orage-related macular degeneration (AMD), rheumatoid arthritis, andpsoriasis (Folkman et al., J. Biol. Chem. 267:10931-10934 (1992);Klagsbrun et al., Annu. Rev. Physiol. 53:217-239 (1991); and Garner A,“Vascular Diseases”. In: Pathobiology of ocular disease. A dynamicapproach. Garner A, Klintworth G K, Eds. 2nd Edition Marcel Dekker, NY,pp 1625-1710 (1994)). For example, vascularization allows tumor cells insolid tumors to acquire a growth advantage and proliferative freedom ascompared to normal cells. Accordingly, a correlation has been observedbetween microvessel density in tumors and patient survival with variouscancers and tumors (Weidner et al., N Engl J Med 324:1-6 (1991); Horaket al., Lancet 340:1120-1124 (1992); and Macchiarini et al., Lancet340:145-146 (1992)).

A number of RTK have been identified that govern discrete stages ofvascular development (Folkman et al., Cell, 87:1153-1155 (1996);Hanahan, D., Science, 277:48-50 (1997); Risau, W., Nature, 386:671-674(1997); Yancopoulos et al., Cell, 93:661-664 (1998)). For example,VEGFR2 (FLK1), a receptor for vascular endothelial growth factor (VEGF),mediates endothelial and hematopoietic precursor cell differentiation(Shalaby et al., Nature, 376:62-66 (1995); Carmeliet et al., Nature,380:435-439 (1996); Ferrara et al., Nature 380:439-442 (1996)). VEGFalso governs later stages of angiogenesis through ligation of VEGFR1(FLT1) (Fong et al., Nature, 376:66-70 (1995)). Mice that lack VEGFR1have disorganized vascular endothelium with ectopic occurrence ofendothelial cells from the earliest stages of vascular development,suggesting that VEGFR1 signaling is essential for the proper assembly ofendothelial sheets (Fong et al., supra). Another tyrosine kinasereceptor, TEK (TIE2) (Dumont et al., Genes Dev. 8:1897-1909 (1994); Satoet al., Nature, 376:70-74 (1995)) and its ligands ANG1 (Davis et al.,Cell 87:1161-1169 (1996); Suri et al., Cell 87:1171-1180 (1996)) andANG2 (Maisonpierre et al., Science 277:55-60 (1997)) are involved inassembly of non-endothelial vessel wall components. TIE (TIE1) isinvolved in maintaining endothelial integrity, and its inactivationresults in perinatal lethality due to edema and hemorrhage (Sato, etal., Nature 376:70-74 (1995)). The TEK pathway seems to be involved inmaturation steps and promotes interactions between the endothelium andsurrounding vessel wall components (Suri et al., supra; and Vikkula etal., Cell 87:1181-1190 (1996)).

The EPH tyrosine kinase subfamily appears to be the largest subfamily oftransmembrane RTK (Pasquale et al., Curr. Opin. Cell Biol. 9:608-615(1997); and Orioli and Klein, Trends in Genetics 13:354-359 (1997)).Ephrins and their EPH receptors govern proper cell migration andpositioning during neural development, presumably through modulatingintercellular repulsion (Pasquale, supra; Otioli and Klein, supra).Bidirectional signaling has been observed for some Ephrin-B/EPHBligand/receptor pairs (Holland et al., Nature 383:722-725 (1996); andBruckner et al., Science 275:1640-1643 (1997)). For example, Ephrin-A1and Ephrin-B1 have been proposed to have angiogenic properties (Pandeyet al., Science 268:567-569 (1995); and Stein et al., Genes Dev.12:667-678 (1998)). Ephrin-B2, a ligand for EPHB4 receptor, was recentlyreported to mark the arterial compartment during early angiogenesis, andmice that lack Ephrin-B2 showed severe anomalies in capillary bedformation (Wang et al., Cell 93: 741-753 (1998)).

It is known that some compounds possess an ability to inhibit a tyrosinekinase activity. In particular, WO 2004 discloses imidazole and pyridinderivatives as tyrosine kinase inhibitors.

Thus, modulating tyrosine kinase activity by chemical compoundsrepresents a rational, targeted approach to cancer therapy.Additionally, because tyrosine kinases have a number of other diversebiological functions, such as regulation of metabolism, celldifferentiation, inflammation, immune responses, and tissuemorphogenesis, kinases are attractive for drug development outsideoncology.

3. SUMMARY

Provided are compounds that modulate tyrosine kinase activity,compositions that comprise the compounds and methods of using thecompounds for the treatment or prevention of diseases or conditions thatare characterized by tyrosine kinase activity or expression including,for example, cancer, diabetes, restenosis, arteriosclerosis, psoriasis,angiogenic diseases and immunologic disorders. (see, e.g., Powis et al.,1994, Anti-Cancer Drugs Design 9: 263-277; Merenmies et al., 1997, CellGrowth Differ 8: 3-10; Shawver et al., 1997, Drug Discovery Today2:50-63; the contents of each are hereby incorporated by reference intheir entireties). The compounds provided herein are described below indetail.

Provided are compounds according to formula (1), or a stereoisomer,tautomer, salt, hydrate or prodrug thereof:

wherein X¹, X², X³, X⁴, X⁵, X⁶, W¹, W², W³, W⁴, W¹, W⁶, Y¹, Y² and R¹are as defined below. In the description below, all combinations of therecitations for X¹, X², X³, X⁴, X⁵, X⁶, W¹, W², W³, W⁴, W⁵, W⁶, Y¹, Y²and R¹ are within the scope of this disclosure. Other embodiments areset forth below.

3.1. Definitions

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.When two terms referring to chemical groups are combined, the combinedterm refers to the groups covalently linked in either orientation,unless specified otherwise. For instance, the term “acylamino” can referto either “—C(O)—N(R)—” or to “—N(R)—C(O)—” unless specified otherwiseand similarly sulfonamido or aminosulfonyl can refer to either—S(O₂)—N(R)— or —N(R)—S(O₂)—.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Aliphatic” refers to hydrocarbyl organic compounds or groupscharacterized by a straight, branched or cyclic arrangement of theconstituent carbon atoms and an absence of aromatic unsaturation.Aliphatics include, without limitation, alkyl, alkylene, alkenyl,alkenylene, alkynyl and alkynylene. Aliphatic groups typically have from1 or 2 to about 12 carbon atoms.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups, inone embodiment having up to about 11 carbon atoms, in anotherembodiment, as a lower alkyl, from 1 to 8 carbon atoms, and in yetanother embodiment, from 1 to 6 carbon atoms. The hydrocarbon chain maybe either straight-chained or branched. This term is exemplified bygroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term “loweralkyl” refers to alkyl groups having 1 to 6 carbon atoms. The term“alkyl” also includes “cycloalkyl” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and in one embodiment refers to an alkyl grouphaving 1 or more substituents, in another embodiment, from 1 to 5substituents, and yet in another embodiment, from 1 to 3 substituents,selected from the group consisting of acyl, acylamino, acyloxy, alkoxy,substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy,aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substitutedcycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, alkylthio,substituted alkylthio, arylthio, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂—, and aryl-S(O)₂—.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groups inone embodiment having up to about 11 carbon atoms and in anotherembodiment having 1 to 6 carbon atoms which can be straight-chained orbranched. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving in one embodiment 1 or more substituents, in another embodimentfrom 1 to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, halogen, hydroxyl, keto, nitro, alkylthio, substituted alkylthio,arylthio, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups having in one embodiment up to about 11 carbon atoms, in anotherembodiment from 2 to 8 carbon atoms, and in yet another embodiment from2 to 6 carbon atoms, which can be straight-chained or branched andhaving at least 1 and particularly from 1 to 2 sites of olefinicunsaturation. Particular alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), isopropenyl (—C(CH₃)═CH₂), vinyl andsubstituted vinyl, and the like.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having in one embodiment up to about 11 carbon atomsand in another embodiment 2 to 6 carbon atoms which can bestraight-chained or branched and having at least 1 and particularly from1 to 2 sites of olefinic unsaturation. This term is exemplified bygroups such as ethenylene (—CH═CH—), the propenylene isomers (e.g.,—CH═CHCH₂— and —C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically unsaturated hydrocarbyl groupsparticularly having in one embodiment up to about 11 carbon atoms and inanother embodiment 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude acetylenic, ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” as used herein, which can include “acyl”, refers to the groupR—C(O)—, where R is hydrogen or alkyl as defined above.

“Alkoxy” refers to the group —OR where R is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and yet in another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl,hydroxyl, keto, nitro, alkylthio, substituted alkylthio, arylthio,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Heteroalkyl” refers to an alkyl chain as specified above, having one ormore heteroatoms selected from O, S, or N.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted in one embodiment with 1 or more substituents,in another embodiment from 1 to 5 substituents, and in yet anotherembodiment from 1 to 3 substituents, selected from the group consistingof acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl,substituted alkynyl, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro,alkylthio, substituted alkylthio, arylthio, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring. In certainembodiments, a bicyclic compound of the invention comprises a fusedaryl.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R)₂ whereeach R is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, and whereboth R groups are joined to form an alkylene group. When both R groupsare hydrogen, —N(R)₂ is an amino group.

“Azido” refers to the radical —N₃.

“Carbamoyl” refers to the radical —C(O)N(R)₂ where each R group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving in one embodiment 1 or more substituents, in another embodimentfrom 1 to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR where R is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having in one embodiment 1 or more substituents, inanother embodiment from 1 to 5 substituents, and in yet anotherembodiment from 1 to 3 substituents, selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C≡C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Particularhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” or “heteroaromatic” refers to a monovalent heteroaromaticgroup derived by the removal of one hydrogen atom from a single atom ofa parent heteroaromatic ring system. Typical heteroaryl groups include,but are not limited to, groups derived from acridine, arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, tetrahydroisoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, tetrahydroquinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. Particularly, heteroaryl can includeother saturated ring systems, and can therefore be derived fromindoline, indolizine, tetrahydroquinoline, and tetrahydroisoquinoline.In certain embodiments, the heteroaryl group is between 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being useful in certainembodiments. Particular heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,pyrimidine, quinoline, tetrahydroquinoline, isoquinoline,tetrahydroisoquinoline, imidazole, oxazole and pyrazine.

As used herein, the term “cycloheteroalkyl” refers to a stableheterocyclic non-aromatic ring and fused rings containing one or moreheteroatoms independently selected from N, O and S. A fused heterocyclicring system may include carbocyclic rings and need only include oneheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein. Incertain embodiments, “substituted sulfanyl” refers to a radical —SRwhere R is an alkyl or cycloalkyl group as defined herein that may beoptionally substituted as defined herein. Alkylthio or arylthio refer tothe above sulfanyl group. Representative examples include, but are notlimited to, methylthio, ethylthio, propylthio, butylthio, phenylthio andthe like.

“Sulfinyl” refers to the radical —S(O)H. “Substituted sulfinyl” refersto a radical such as S(O)—R wherein R is any substituent describedherein.

“Sulfonyl” refers to the divalent radical —S(O₂)—. “Substitutedsulfonyl” refers to a radical such as —S(O₂)—R wherein R is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O₂)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R₂N(O₂)S— wherein each R isindependently any substituent described herein. In particularembodiments, R is selected from H, lower alkyl, alkyl, aryl andheteroaryl.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms as long as the heteroaromatic ring is chemically feasibleand stable.

“Pharmaceutically acceptable salt” refers to any salt of a compound ofthis invention which retains its biological properties and which is nottoxic or otherwise undesirable for pharmaceutical use. Such salts may bederived from a variety of organic and inorganic counter-ions well knownin the art and include. Such salts include: (1) acid addition saltsformed with organic or inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic,trifluoroacetic, trichloroacetic, propionic, hexanoic,cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic,succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric,benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic,phthalic, lauric, methanesulfonic, ethanesulfonic,1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic,4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic,camphoric, camphorsulfonic,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic,3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric,gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic,cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2)salts formed when an acidic proton present in the parent compound either(a) is replaced by a metal ion, e.g., an alkali metal ion, an alkalineearth ion or an aluminum ion, or alkali metal or alkaline earth metalhydroxides, such as sodium, potassium, calcium, magnesium, aluminum,lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with anorganic base, such as aliphatic, alicyclic, or aromatic organic amines,such as ammonia, methylamine, dimethylamine, diethylamine, picoline,ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium and the like, and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, besylate, acetate, maleate, oxalate and the like. The term“physiologically acceptable cation” refers to a non-toxic,physiologically acceptable cationic counterion of an acidic functionalgroup. Such cations are exemplified by sodium, potassium, calcium,magnesium, ammonium and tetraalkylammonium cations and the like.

“Solvate” refers to a compound of the present invention or a saltthereof, that further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

It is to be understood that compounds having the same molecular formulabut differing in the nature or sequence of bonding of their atoms or inthe arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, when it is bonded to four different groups, a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is designated (R) or(S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew.Chem. 78:413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew.Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem.94:614-631, Angew. Chem. Internat. Ed. Eng. 21:567-583; Mata and Lobo,1993, Tetrahedron:Asymmetry 4:657-668) or can be characterized by themanner in which the molecule rotates the plane of polarized light and isdesignated dextrorotatory or levorotatory (i.e., as (+)- or (−)-isomers,respectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of enantiomers is called a “racemic mixture”.

In certain embodiments, the compounds of this invention may possess oneor more asymmetric centers; such compounds can therefore be produced asthe individual (R)- or (S)-enantiomer or as a mixture thereof. Unlessindicated otherwise, for example by designation of stereochemistry atany position of a formula, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Methods for determination of stereochemistry and separation ofstereoisomers are well-known in the art. In particular embodiments, thepresent invention provides the stereoisomers of the compounds depictedherein upon use of stereoisomerically pure intermediates in theirsynthesis, such as pure enantiomers, or diastereomers as buildingblocks, prepared by chiral synthesis methodologies, or resolution byformation of diastereomeric salts with chiral acid or base and theirseparation, or separation by means of chromatography, including usingchiral stationary phase. The racemic, or diastereomeric mixtures ofembodiments (compounds) in this invention can also be separated by meansof chromatography, including chiral stationary phase chromatography.

In certain embodiments, the compounds of the invention are“stereochemically pure.” A stereochemically pure compound has a level ofstereochemical purity that would be recognized as “pure” by those ofskill in the art. Of course, this level of purity will be less than100%. In certain embodiments, “stereochemically pure” designates acompound that is substantially free of alternate isomers. In particularembodiments, the compound is 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, 99.5% or 99.9% free of other isomers.

As used herein, the terms “disorder” and “disease” are usedinterchangeably to refer to a condition in a subject. Certain conditionsmay be characterized as more than one disorder. For example, certainconditions may be characterized as both non-cancerous proliferativedisorders and inflammatory disorders.

As used herein, the term “effective amount” refers to the amount of acompound of the invention which is sufficient to reduce or amelioratethe severity, duration of a disorder, cause regression of a disorder,prevent the recurrence, development, or onset of one or more symptomsassociated with a disorder, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

As used herein, the term “in combination” refers to the use of more thanone therapies. The use of the term “in combination” does not restrictthe order in which therapies (e.g., prophylactic and/or therapeuticagents) are administered to a subject with a disorder. A first therapycan be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapy to a subject witha disorder.

As used herein, the terms “prophylactic agent” and “prophylactic agents”as used refer to any agent(s) which can be used in the prevention of adisorder or one or more symptoms thereof. In certain embodiments, theterm “prophylactic agent” refers to a compound of the invention. Incertain other embodiments, the term “prophylactic agent” does not refera compound of the invention. In certain embodiments, a prophylacticagent is an agent which is known to be useful for, or has been or iscurrently being used to the prevent or impede the onset, development,progression and/or severity of a disorder. Prophylactic agents may becharacterized as different agents based upon one or more effects thatthe agents have in vitro and/or in vivo. For example, an anti-angiogenicagent may also be characterized as an immunomodulatory agent.

As used herein, the terms “prevent,” “preventing” and “prevention” referto the prevention of the recurrence, onset, or development of one ormore symptoms of a disorder in a subject resulting from theadministration of a therapy, or the administration of a combination oftherapies.

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a therapy which is sufficient to result in the preventionof the development, recurrence or onset of one or more symptomsassociated with a disorder, or to enhance or improve the prophylacticeffect(s) of another therapy.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to ananimal, in certain embodiments a mammal including a non-primate (e.g., acow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkeysuch as a cynomolgous monkey, a chimpanzee and a human), and moreparticularly a human. In another embodiment, the subject is a farmanimal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or acat). In certain embodiments, the subject is a human.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy which has been or iscurrently being used to prevent, manage or treat a disorder, which ismore effective than the additive effects of the therapies. A synergisticeffect of a combination of therapies permits the use of lower dosages ofone or more of the therapies and/or less frequent administration of saidtherapies to a subject with a disorder. The ability to utilize lowerdosages of a therapy and/or to administer said therapy less frequentlyreduces the toxicity associated with the administration of said therapyto a subject without reducing the efficacy of said therapy in theprevention, management or treatment of a disorder. In addition, asynergistic effect can result in improved efficacy of agents in theprevention, management or treatment of a disorder. Finally, asynergistic effect of a combination of therapies may avoid or reduceadverse or unwanted side effects associated with the use of eithertherapy alone.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment, management, oramelioration of a disorder or one or more symptoms thereof. In certainembodiments, the term “therapeutic agent” refers to a compound of theinvention. In certain other embodiments, the term “therapeutic agent”refers does not refer to a compound of the invention. In certainembodiments, a therapeutic agent is an agent which is known to be usefulfor, or has been or is currently being used for the treatment,management, prevention, or amelioration a disorder or one or moresymptoms thereof. Therapeutic agents may be characterized as differentagents based upon one or more effects the agents have in vivo and/or invitro, for example, an anti-inflammatory agent may also be characterizedas an immunomodulatory agent.

As used herein, the term “therapeutically effective amount” refers tothat amount of a therapy sufficient to result in the amelioration of oneor more symptoms of a disorder, prevent advancement of a disorder, causeregression of a disorder, or to enhance or improve the therapeuticeffect(s) of another therapy. In a specific embodiment, with respect tothe treatment of cancer, an effective amount refers to the amount of atherapy that inhibits or reduces the proliferation of cancerous cells,inhibits or reduces the spread of tumor cells (metastasis), inhibits orreduces the onset, development or progression of one or more symptomsassociated with cancer, or reduces the size of a tumor. In certainembodiments, a therapeutically effective of a therapy reduces theproliferation of cancerous cells or the size of a tumor by at least 5%,at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 99%, relative to acontrol or placebo such as phosphate buffered saline (“PBS”).

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a disorder or oneor more symptoms thereof. In certain embodiments, the terms “therapy”and “therapies” refer to chemotherapy, radiation therapy, hormonaltherapy, biological therapy, and/or other therapies useful in theprevention, management, treatment or amelioration of a disorder or oneor more symptoms thereof known to one of skill in the art (e.g., skilledmedical personnel).

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disorder, or the amelioration of one or more symptomsthereof resulting from the administration of one or more therapies.

As used herein, the term “modulation” or “modulating” refers to thealteration of the catalytic activity of a tyrosine kinase. Inparticular, modulating can refer to the activation or to the inhibitionof the tyrosine kinase. The tyrosine kinase can be any tyrosine kinaseknown to those of skill in the art. In certain embodiments, the tyrosinekinase is a receptor tyrosine kinase or an intracellular tyrosinekinase.

The definitions used herein are according to those generally accepted inthe art and those specified herein.

Abbreviations used herein are standard abbreviations used in the art oforganic chemistry:

AcOH—acetic acidTFA—trifluoroacetic acidDMSO—dimethyl sulfoxideDCM—dichlomethaneBOC—tert. ButyloxycarbonylTHF—tetrahydrofuranp-TOS—p-ToluenesulfonylTEA—triethylamineETOH—ethanolMeOH—methanolDIPEA—diisopropylethylamine

4. DETAILED DESCRIPTION 4.1. Compounds

In one aspect, provided are compounds according to formula (1), or astereoisomer, tautomer, salt or hydrate thereof:

In formula (1), each W¹ through W⁶ is independently a carbon atom or anitrogen atom. When any W¹ through W⁶ is N, then the correspondingsubstituent(s) X¹ through X⁶ is (are) absent.

Compounds according to formula (1) can also be depicted in theirrespective “keto” form, which under certain conditions may predominateover the corresponding “enol” form. However, all possible tautomers andstereoisomers (such as for example, but not limited to: E and Z, (transand cis) are incorporated herein. Examples of the tautomers of Formula(1) include, but are not limited to:

In formula (1), each X¹ through X³, X⁵ and X⁶ is independently selectedfrom hydrogen, hydroxy, halogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, optionally substituted acylamino,optionally substituted sulfonamido, optionally substituted ureido,trifluoromethyl, trifluoromethoxy, nitro, cyano, optionally substitutedaryl or heteroaryl, aryloxy or heteroaryloxy, arylamino orheteroarylamino (substituted by one or more groups selected from loweralkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, carboxamide, sulfonamide, sulfamide, ureido,methylenedioxy, ethylenedioxy, primary, secondary or tertiary amino,mono or dialkyl amido, heterocyclylamido, optionally substitutedheterocyclyl or cycloalkyl, optionally substituted heterocyclylalkyl,heteroalkyl), nitrogen-heterocyclyl, connected either by its nitrogen,or a carbon atom (such as piperazino, homopiperazino, morpholino,thiomorpholino, thiomorpholino-5-oxide, thiomorpholino-S,S-dioxide,pyrrolidino, piperidino, azetidino), nitrogen-heterocyclyl-alkyl,connected either by its nitrogen or a carbon atom (such aspiperazinomethyl, piperazinoethyl, homopiperazinomethyl,morpholinomethyl, thiomorpholinomethyl, thiomorpholino-5-oxide-methyl,thiomorpholino-S,S-dioxide-methyl, pyrrolidinomethyl, piperidinoethyl,azetidinomethyl, all optionally substituted by groups selected fromhydroxyalkyl, lower alkoxyalkyl, primary, secondary, or tertiaryamino-alkyl, lower alkyl cycloalkyl or heterocycloalkyl). Such aryl andheteroaryl groups can be bicyclic in certain embodiments. In the abovelist, lower alkyl, lower alkoxy, acyl amino, sulfonamido and ureido canbe substituted, for example, with aryl, heteroaryl, cycloalkyl orcycloheteroalkyl.

In certain embodiments, any adjacent pair of X¹ through X³ can be joinedto form a cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring fused tothe ring comprising W¹ through W³. Exemplary fused rings includenaphthyl, benzodioxolyl, benzofuranyl, benzodioxinyl,dihydrobenzodioxinyl, quinolinyl, and others that will be recognized bythose of skill in the art.

In formula (1), X⁴ can be selected from hydrogen, hydroxy, halogen,trifluoromethyl, trifluoromethoxy, optionally substituted (alkyl,alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl),optionally substituted (aryl, heteroaryl, arylalkyl, heteroarylalkyl,aryloxy, heteroaryloxy, arylalkoxy, heteroaryalkoxy, arylthio,heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl,heteroarylsulfonyl, arylsulfonamido, heteroarylsulfonamido,arylaminosulfonyl, heteroarylaminosulfonyl, arylamino, heteroarylamino,arylalkylamino, heteroarylalkylamino), by substituents selected fromhydrogen, halogen, hydroxy, amino, cyano, nitro, carboxamido,sulfonamido, alkoxy, amino, lower-alkylamino, di-lower-alkylamino,cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy,trifluoromethyl, trifluoromethoxy, methylenedioxy, ethylenedioxy,methanesulfonyl, trifluoromethanesulfonyl, dialkylaminoalkyl,dialkylaminoalkoxy, heterocyclyl, heteroalkyl and heterocyclylalkyl.

X⁴ is also selected from the following groups:

wherein:

m=1 to 4, n=0 to 4, p=1 to 5; and o=0 to 5.

R² is selected from optionally substituted aryl, or heteroaryl,—(CH₂)_(o)-aryl, —(CH₂)_(o)-heteroaryl, —(CH₂)_(p)-M¹-aryl,—(CH₂)_(p)-M¹-heteroaryl substituted by a substituent independentlyselected from a group consisting of hydrogen, hydroxy, halogen,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethanesulfonyl, 2,2,2-trifluoroethoxy, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, methylenedioxy, ethylenedioxy,trimethylene, dimethyleneoxy, cyano, nitro, primary, secondary ortertiary amino, such as dimethylamino, carboxamide, sulfonamide, loweralkylsulfonyl, lower alkylsulfinyl, lower alkylthio, loweralkylthioalkyl, lower alkylsulfonylalkyl, optionally substituted aryl orheteroaryl, wherein M¹ is a —(CH₂)— or a heteroatom O, S, or N—R*; andR* is selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, acyl,optionally substituted aryl, heteroaryl, alkylsulfonyl or arylsulfonyl;

R³ is selected from optionally substituted aryl, heteroaryl,—(CH₂)_(o)-aryl, —(CH₂)_(o)-heteroaryl, —(CH₂)_(p)-M²-aryl,—(CH₂)_(p)-M²-heteroaryl, substituted by a substituent independentlyselected from a group consisting of hydrogen, hydroxy, halogen,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethanesulfonyl, 2,2,2-trifluoroethoxy, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, methylenedioxy, ethylenedioxy,trimethylene, dimethyleneoxy, cyano, nitro, primary, secondary ortertiary amino, such as dimethylamino, carboxamide, sulfonamide, loweralkylsulfonyl, lower alkylsulfinyl, lower alkylthio, loweralkylthioalkyl, lower alkylsulfonylalkyl, optionally substituted aryl orheteroaryl, wherein M² is a heteroatom O, S, or N—R**; and

R** is selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, acyl,optionally substituted aryl, heteroaryl, alkylsulfonyl or arylsulfonyl.

In formula (1), in certain embodiments, each (CH₂)_(m) or (CH₂), can beoptionally substituted with one or more groups selected from hydrogen,halogen, hydroxy, carboxamido, lower alkylcarbonyl, hydroxy-lower alkyl,hydroxycycloalkyl, optionally substituted (primary, secondary ortertiary amino, lower alkoxy, lower alkyl, lower heteroalkyl,cycloalkyl, heterocyclo, heterocycloalkyl, aryl, heteroaryl, aryloxy orheteroaryloxy), by groups selected from halogen, hydroxy, amino, loweralkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, trifluoromethanesulfonyl, cyano, nitro,carboxamido, lower alkylthio, lower alkylsulfoxy, lower alkylsulfonyl,arylthio, arylsulfoxy, arylsulfonyl, lower alkylcarbonyl, arylcarbonyl)all groups optionally substituted by groups selected from hydrogen,halogen, lower alkyl, trifluoromethyl, trifluoromethoxy, lower alkoxy,lower alkylthio, hydroxy, sulfonamido, lower acylamino. In certainembodiments the (CH₂)_(m) or (CH₂)_(n) can form a cyclic structure. Inaddition, in certain embodiments, one or more methylene of (CH₂)_(m) or(CH₂)_(m) can be replaced by a heteroatom selected from O, NH or N-loweralkyl and S, where appropriate according to the judgment of one of skillin the art.

In certain embodiments according to formula (1), the substituent X⁴ isselected from the following groups:

wherein:

L is selected from O, S, N—R#₉;

R#₉ is selected from hydrogen, lower alkyl, cycloalkyl, alkenyl,alkynyl, heteroalkyl, heterocyclyl, optionally substituted aryl,heteroaryl, arylalkyl, heteroarylalkyl by groups selected from hydrogen,halogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy,lower alkylthio, nitro, azido, cyano, amido and ureido; and

each X* is independently selected from hydrogen, lower alkyl, halogen,lower alkoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy,trifluoromethylthio, azido, cyano, nitro, methylenedioxy, trimethyleneand dimethyleneoxy.

In another embodiment in formula (1), X⁴ is selected from the following:

wherein:

X*A is hydrogen, halogen, optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano;

X*B is hydrogen, halogen, optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano;

X*C is hydrogen, halogen, optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano;

X*D is hydrogen, halogen, optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano;

X*E is hydrogen, halogen, optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano;

X*B and X*C or independently X*C and X*D or independently X*D and X*Ecan form a 5 to 7 membered ring, containing one or two heteroatoms suchas oxygen, sulfur or nitrogen, (optionally substituted with a loweralkyl group), such as for example, but not limited to methylenedioxy,ethylenedioxy, propylenedioxy, dimethyleneoxy (dihydrobenzofuran ring),all optionally mono- or di-substituted and their partially, or fullyfluorinated derivatives, including difluoromethylenedioxy; and

X*B and X*C or independently X*C and X*D or independently X*D and X*Ecan form an optionally substituted condensed aromatic or heteroaromaticring, for example, but not limited to 1- or 2-naphthyl, 4-, 5-, 6- or7-indolyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-thianaphthenyl,carbazolyl by groups selected from lower alkyl, lower alkoxy, halogen,trifluoromethyl, cyano, or nitro.

In another embodiment in formula (1), X⁴ is selected from the following:

wherein:

X*A is lower alkyl, halogen, trifluoromethyl, trifluoromethoxy;

X*B is hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl,trifluoromethoxy, cyano, nitro, dimethylamino, diethylamino;

X*C is hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl,trifluoromethoxy, cyano, nitro, dimethylamino, diethylamino;

X*D is hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl,trifluoromethoxy, cyano, nitro, dimethylamino, diethylamino;

X*E is hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl,trifluoromethoxy, cyano, nitro, dimethylamino, diethylamino;

X*B and X*C or independently X*C and X*D or independently X*D and X*Ecan form a 5 to 7 membered ring, containing one or two heteroatoms suchas oxygen, sulfur or nitrogen, (optionally substituted with a loweralkyl group), such as for example, but not limited to methylenedioxy,ethylenedioxy, propylenedioxy, dimethyleneoxy (dihydrobenzofuran ring),all optionally mono- or di-substituted and their partially, or fullyfluorinated derivatives, including difluoromethylenedioxy; and

X*B and X*C or independently X*C and X*D or independently X*D and X*Ecan form an optionally substituted condensed aromatic or heteroaromaticring, for example, but not limited to 1- or 2-naphthyl, 4-, 5-, 6- or7-indolyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-thianaphthenyl,carbazolyl by groups selected from lower alkyl, lower alkoxy, halogen,trifluoromethyl, cyano, or nitro.

In another embodiment in formula (1), each W¹ through W⁶ isindependently selected from carbon or nitrogen.

In another embodiment in formula (1), Y¹ is independently selected from:

wherein:

q is an integer from 0 to 4; and

R#₁₀ is selected from hydrogen, lower alkyl, hydroxy and lower alkoxy.

In formula (1), in certain embodiments, each (CH₂)_(q) can be optionallysubstituted with one or more groups selected from hydrogen, lower alkyl,heteroalkyl, heterocyclo, hydroxy-lower alkyl, cycloalkyl,hydroxycycloalkyl. In certain embodiments, such substituents can bejoined to form a cyclic structure. In certain embodiments, one or moreof the methylene groups of (CH₂)_(q) can be replaced by a carbonyl group(C═O).

In yet another embodiment in formula (1), Y¹ is independently selectedfrom:

In another embodiment in formula (1), Y² is independently selected from:

wherein:

r is an integer from 0 to 4; and

R#₁₁ is selected from hydrogen, lower alkyl, hydroxy and lower alkoxy.

In formula (1), in certain embodiments, each (CH₂)_(r) can be optionallysubstituted with one or more groups selected from hydrogen, lower alkyl,heteroalkyl, heterocyclo, hydroxy-lower alkyl, cycloalkyl,hydroxycycloalkyl. In certain embodiments, such substituents can bejoined to form a cyclic structure. In certain embodiments, one or moreof the methylene groups of (CH₂)_(r) can be replaced by a carbonyl group(C═O).

In yet another embodiment in formula (1), Y² is independently selectedfrom:

In another embodiment in formula (1), R¹ is independently selected fromoptionally substituted heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, heterocyclyloxyalkyl, heteroalkyl,heterocyclylaminoalkyl, aminoalkyl, lower alkylaminoalkyl, di-(loweralkyl)-aminoalkyl, aminocycloalkyl, alkylaminocycloalkyl, di-(loweralkyl)-aminocycloalkyl, di-(lower alkyl)-aminocycloalkylalkyl, by groupsselected from hydrogen, lower alkyl, hydroxy, lower alkoxy, amino,amidino, carboxamido, sulfonamido, hydroxy, cyano, primary, secondary ortertiary amino, halo, azido, lower alkoxyalkyl, cyanoalkyl, azidoalkyl,haloalkyl, hydroxyalkyl, methanesulfonylalkyl, primary, secondary ortertiary amino-alkyl, optionally substituted aryl, heteroaryl,heteroalkyl, heterocyclyl, cycloalkyl, alkenyl and alkynyl.

In another embodiment in formula (1), R¹ is independently selected fromoptionally substituted heterocyclyl, heterocyclylalkyl, aminoalkyl,lower alkylaminoalkyl and di-(lower alkyl)-aminoalkyl.

In another embodiment in formula (1), exemplary R¹ include, but are notlimited to:

wherein:

R¹³ is selected from hydrogen, lower alkyl, heteroalkyl, heterocyclyl,cycloalkyl and heterocycloalkyl;

R¹⁴ is selected from hydrogen, hydroxy, lower alkoxy, di-(loweralkyl)amino, lower alkyl, heteroalkyl, heterocyclyl, cycloalkyl,heterocycloalkyl, lower alkoxyalkyl, cyanoalkyl, azidoalkyl, nitroalkyl,ketoalkyl, methanesulfonylalkyl, aminoalkyl, lower alkylaminoalkyl,di-(lower alkyl)aminoalkyl, optionally substituted aryl, heteroaryl,arylalkyl, heteroarylalkyl;

R¹⁵ is selected from hydrogen, amino, lower alkylamino, di-(loweralkyl)amino, hydroxy, lower alkoxy, heteroalkyl, lower alkoxyalkyl,aminoalkyl, lower alkylaminoalkyl and di-(lower alkyl)aminoalkyl;

a is an integer from 0 to 4; and

t, u, v are independent integers from 0 to 5. It is understood that ifany of the integers is (are) 0 (zero), it means a covalent chemicalbond.

In another embodiment, R¹ is further selected from:

In R¹, in certain embodiments, the methylene chain between theconnection and the heteroatom may be optionally substituted by one ormore hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy,carboxamido or sulfonamido and one of the methylene groups can besubstituted by a heteroatom, such as O, NR*** or S, S═O, or S(═O)₂,wherein R*** is selected from hydrogen, hydroxy, lower alkyl, loweralkoxy, heteroalkyl, hydroxyalkyl, aminoalkyl, lower alkylaminoalkyl anddi-(lower alkyl)aminoalkyl. Any of the ring systems can also beoptionally substituted by a lower alkyl or heteroalkyl group.

In another embodiment, the compounds have the following formula:

wherein W¹ is nitrogen or carbon.

The substituents are defined as described herein.

In another embodiment, the compounds have the following formulas:

The substituents are defined as described above.

In another embodiments, compounds correspond to the following formulas:

whereinX²⁰ to X²⁴ are each independently selected from hydrogen, lower alkyl,lower alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano,nitro, ureido, primary, secondary or tertiary amino, methylenedioxy,ethylenedioxy and difluoromethylenedioxy.

The other compounds include those corresponding to formulas 1l-1o,wherein:

X²⁰=methyl; X²¹=chloro; X²²=X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹=methyl; X²²=X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹=methoxy; X²²=X²³=X²⁴=hydrogen;X²⁰=chloro; X²¹=methyl; X²²=X²¹=X²⁴=hydrogen;X²⁰=methyl; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=ethyl; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=isopropyl; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=chloro; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=bromo; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=iodo; X²¹=X²²=X²³=X²⁴=hydrogen;X²⁰=bromo; X²¹=fluoro; X²²=X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹=methoxy; X²²=methyl; X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹=hydrogen; X²²=methyl; X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹=X²²=methyl; X²³=X²⁴=hydrogen;X²⁰=bromo; X²¹=hydrogen; X²²=methyl; X²³=X²⁴=hydrogen;X²⁰=chloro; X²¹-X²²=methylenedioxy; X²³=X²⁴=hydrogen;X²⁰=methyl; X²¹-X²²=methylenedioxy; X²³=X²⁴=hydrogen;X²⁰=ethyl; X²¹-X²²=methylenedioxy; X²³=X²⁴=hydrogen;X²⁰=hydrogen; X²¹-X²²=methylenedioxy; X²³=hydrogen; X²⁴=chloro;X²⁰=hydrogen; X²¹-X²²=methylenedioxy; X²³=hydrogen; X²⁴=methyl;X²⁰=hydrogen; X²¹-X²²=methylenedioxy; X²³=hydrogen; X²⁴=ethyl;X²⁰=chloro; X²¹=fluoro; X²²=X²³=hydrogen; X²⁴=fluoro;X²⁰ bromo; X²¹=fluoro; X²²=X²³=hydrogen; X²⁴=fluoro;X²⁰=methyl; X²¹=fluoro; X²²=X²³=hydrogen; X²⁴=fluoro;X²⁰=ethyl; X²¹=fluoro; X²²=X²³=hydrogen; X²⁴=fluoro;X²⁰=methyl; X²¹=fluoro; X²²=hydrogen; X²³=fluoro; X²⁴=hydrogen;X²⁰=chloro; X²¹=fluoro; X²²==hydrogen; X²³=fluoro; X²⁴=hydrogen;X²⁰=chloro; X²¹=hydrogen; X²³=X²⁴=hydrogen; andX²⁰=bromo; X²¹=hydrogen; X²²=X²³=fluoro; X²⁴=hydrogen.

In another embodiment, the compounds correspond to the followingformulas:

whereinX³⁰ to X³⁴ are independently selected from hydrogen, lower alkyl, loweralkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano,nitro, ureido, primary, secondary or tertiary amino, methylenedioxy,ethylenedioxy and difluoromethylenedioxy.

Other compounds include those corresponding to formulas 1p to 1s,wherein:

X³⁰=X³¹=X³²=X³³=X³⁴=hydrogen;X³⁰=methyl; X³¹=X³²=X³³=X³⁴=hydrogen;X³⁰=chloro; X³¹=X³²=X³³=X³⁴=hydrogen;X³⁰=hydrogen; X³¹=chloro; X³²=X³³=X³⁴=hydrogen;X³⁰=X³¹=hydrogen; X³²=chloro; X³³=X³⁴=hydrogen;X³⁰=hydrogen; X³¹=methoxy; X³²=X³³=X³⁴=hydrogen;X³⁰=X³¹=hydrogen; X³²=methoxy; X³³=X³⁴=hydrogen;X³⁰=methyl; X³¹=hydrogen; X³²=methyl; X³³=X³⁴=hydrogen; andX³⁰=methyl; X³¹=X³²=hydrogen; X³³=fluoro; X³⁴=hydrogen.

In another embodiments, compounds correspond to the following formulas:

whereinX⁴⁰ to X⁴⁴ are independently selected from hydrogen, lower alkyl, loweralkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoromethoxy, heteroalkyl, cycloalkyl, heterocycloalkyl,cyano, nitro, ureido, primary, secondary or tertiary amino,methylenedioxy, ethylenedioxy and difluoromethylenedioxy.

Such compounds include those corresponding to formulas 1t to 1w,wherein:

X⁴⁰=X⁴¹=X⁴²=X⁴³=X⁴⁴=hydrogen;X⁴⁰=methyl; X⁴¹=X⁴²=X⁴³=X⁴⁴=hydrogen;X⁴⁰=chloro; X⁴¹=X⁴²=X⁴³=X⁴⁴=hydrogen;X⁴⁰=hydrogen; X⁴¹=chloro; X⁴²=X⁴³=X⁴⁴=hydrogen;X⁴⁰=X⁴¹=hydrogen; X⁴²=chloro; X⁴³=X⁴⁴=hydrogen;X⁴⁰=hydrogen; X⁴¹=methoxy; X⁴²=X⁴³=X⁴⁴=hydrogen;X⁴⁰=X⁴¹=hydrogen; X⁴²=methoxy; X⁴³=X⁴⁴=hydrogen;X⁴⁰=methyl; X⁴¹=hydrogen; X⁴²=methyl; X⁴³=X⁴⁴=hydrogen; andX⁴⁰=methyl; X⁴¹=X⁴²=hydrogen; X⁴³=fluoro; X⁴⁴=hydrogen.

In another embodiment, the compounds are:

(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-(pyrrolidin-1-yl)propyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(2-bromophenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(6-ethylbenzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(2-chloro-4-methoxyphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-(3-oxobutyl)piperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one4.2. Preparation of the Compounds

Compounds according to formula (1) can be prepared according to anymethod apparent to those of skill in the art. Provided below areexemplary methods for their preparation.

4.2.1 Procedure for the synthesis of substitutedImidazo[4,5-f]isoindole-5,7(1H,6H)-diones and substituted6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one derivatives (C,C′)

In certain embodiments, compounds of formula (1) are prepared accordingto the following procedures, according to scheme 1.

Scheme 1 describes the preparation of the tricycles. The startingdiamino phthalimides and/or diaminolactams B (and/or their derivatives)are available by the synthetic methodologies described below. The methodis general and is applicable to a variety of derivatives with differentgroups R¹, Y¹ and Y², as well as various X¹ through X⁶ and W¹ throughW⁶.

Condensations of the suitable aromatic, or heteroaromatic aldehydes (A,A′) with the diamino-heterocycles (B) give in the presence of air, or asuitable oxidant the desired substituted aromatic heterotricycles (C,C′). In the addition of exposure to air, use of palladium on charcoal,Raney nickel, or dehydrogenating agents, such as sulfur, Oxone^(R),ferric chloride, sodium bisulfite, benzoquinone, or its derivatives andthe like will also accomplish dehydrogenation of the initially formeddihydroderivatives to the aromatic heterotricycles (C, C′). Othermethods for cyclization of benzimidazole-type derivatives are known inthe art and can be utilized in the formation of the presentheterotricyclic compounds, by way of example, but not limited to:acylation of the diamines (B) with an activated form of the carboxylicacids (D, D′), such as acid chlorides, fluorides, imidazolides, DCC, orDIC and related adducts with the diamine (B), followed by formation ofthe imidazole ring in acidic, or basic conditions (e.g.: heating inacetic acid, or in alcoholic potassium, or sodium methoxide, or use ofPPA, or POCl₃ in the presence of pyridine, or diisopropylethylamine, togive (C,C′). Alternatively, the 2-nitroamine (E) can be used for theacylation step, followed by reduction with titanium trichloride, orstannous chloride solution, followed by cyclization of the monoacyldiamine in acidic, or basic conditions (e.g.: heating in acetic acid, orin alcoholic potassium, or sodium methoxide, or use of PPA, or POCl₃ inthe presence of pyridine, or diisopropylethylamine, to give (C,C′).Carboxylic acids (D,D′) are accessible by methods known in the art,including Kolbe synthesis, carboxylation of the corresponding lithiumcarbanions (preferably in a protected form, such as MOM ethers, ormethoxy derivatives, followed by deprotection with HCl, or BBr₃) withCO₂, or oxidation of the corresponding aldehydes (A,A′) with Ag₂O, orsodium chlorite/isobutylene, under standard conditions.

In certain embodiments, compounds of formula (1) are prepared accordingto the following procedures, according to schemes 2-20.

Description of a substituent as R and R′ means that it may be anychemically feasible substituent, including hydrogen.

Synthesis of Tricyclic DerivativesImidazo[4,5-f]isoindole-5,7(1H,6H)-diones

Substituent Q¹ in Scheme 2 corresponds to the above reaction-compatibleX⁵ of formula (1), especially hydrogen, halogen or methyl. SubstituentQ² in Scheme 2 corresponds to the above reaction-compatible X⁶ offormula (1), especially hydrogen, halogen or methyl. Synthesis of halo-,nitro- and amino-substituted phthalimides can be also found in: E. HWhite and K. Matsuo, JOC, 1967, 1921 and S. Cherkez, J. Herzig, and H.Yellin J. Med. Chem. 1986, 29, 947-959.

Alternatively, 4-chloro-2-methoxy-3-pyridinecarboxaldehyde (A9) or4-bromo-2-methoxy-3-pyridinecarboxaldehyde (A10) can be used in thecyclization of the diamine derivatives (A4) and (A15) to provide thecorresponding tricyclicderivatives—(6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-ones andimidazo[4,5-f]isoindole-5,7(1H,6H)-diones.

(A9) is a highly valuable precursor useful in the synthesis ofbiologically active compounds.

Synthesis of Lactam Derivatives (A14)(6,7-Dihydroimidazo[4,5-f]isoindol-5(1H)-ones)

The 6,7-Dihydroimidazo[4,5-f]isoindol-5(1H)-ones (A14) were synthesizedaccording to two basic methods.

In method A, the fully constructed substituted[4,5-f]isoindole-5,7(1H,6H)-diones (A8) were reduced by zinc in aceticacid to the lactam derivatives.

Synthesis of (6,7-Dihydroimidazo[4,5-f]isoindol-5(1H)-ones) (A14)) shownin Scheme 3.

Synthesis of Lactam Derivatives (A14)(6,7-Dihydroimidazo[4,5-f]isoindol-5(1H)-ones)

In the method B, the nitroamine imide (A3) was reduced by tin andhydrochloric acid to the corresponding diaminolactam (A15), which wasconverted to the iodo-derivative (A16), which was then hydrolyzed by HClto the aminopyridone-lactam chloropyridone derivative (A17). Reaction of(A17) with amines in boiling ethanol and a base such as triethylaminegave the desired target (A14). The conditions are described below. (A17)is a highly valuable precursor useful in the production of biologicallyactive compounds.

Synthesis of 4-chloro-2-methoxy-3-cyanopyridine (A20) and4-chloro-2-methoxy-3-pyridinecarboxaldehyde (A9)

Preparation of 4-bromo-3-cyano-2-methoxypyridine and4-iodo-3-cyano-2-methoxypyridine and the corresponding aldehydes

Thus, 2-chloro-3-cyanopyridine (A18) provided 2-methoxy-3-cyanopyridine(A19) upon treatment with sodium methoxide in methanol. Lithiation ofthe 2-methoxy-3-cyanopyridine (A19) with LDA gave the intermediatecarbanion derivative 4-lithio-2-methoxy-3-cyanopyridine (A21), whichupon treatment with hexachloroethane provided the4-chloro-2-methoxy-3-cyanopyridine (A20). Analogously, reaction withbromine provides the 4-bromo-2-methoxy-3-cyanopyridine (A22) andreaction with iodine provides the 4-iodo-2-methoxy-3-cyanopyridine(A23). All 4-halo-2-methoxy-3-cyanopyridines are highly valuableintermediates, especially for the synthesis of kinase inhibitors.Reduction of the 4-halo-2-methoxy-3-cyanopyridines, for example withDIBAL (diisobutylaluminum hydride) in solvents such as toluene,dichloromethane, or tetrahydrofuran at temperatures ranging from −80° C.to about 80° C., preferably at 20° C. provides after standard workup the4-halo-2-methoxypyridine-3-carboxaldehydes. The4-halo-2-methoxypyridine-3-carboxaldehydes are highly valuable syntheticintermediates. 4-chloro-2-methoxy-3-pyridinecarboxaldehyde (A9) wasprepared in this manner.

4.2.1.1 Preparation of the 2-Methoxy-4-iodopyridine-3-carboxaldehyde

The synthetic methodology is described in the following reference: FangF. G., Xie S., Lowery M. E., J. Org. Chem. 1994, 59, 6142-6143.

4.2.1.2 Preparation of the 4,6-dichloropyrimidine-5-carbaldehyde

The synthesis is described in the following reference: Gomtsyan A. etal. J. Med. Chem., 45 (17), 3639-3648, 2002.

4.2.2 Synthesis of Sultam Derivatives

4.2.3 General Procedure for the Synthesis of Difluorolactam Derivatives

4.2.4 General Procedure for the Synthesis of DihydroisoindoleDerivatives

4.2.5 General Procedure for the Synthesis ofGem-Difluorodihydroisoindole Derivatives

4.2.6 General Procedure for the Synthesis of SubstitutedImino-Dihydroisoindole Derivatives

4.2.7 General Procedure for the Synthesis of SubstitutedDihydroisoindole Derivatives

4.2.8 General Procedure for the Synthesis of SubstitutedDihydroisoindole and Corresponding Spirocompound Derivative

4.2.9 General Procedure for the Synthesis of the Intermediates for theSynthesis of the Compounds of the Invention

AR is an unsubstituted, mono-substituted or polysubstituted aryl orheteroaryl.

4.2.10 General Procedure for the Synthesis of the Intermediates for theSynthesis of the Compounds of the Invention

A is an unsubstituted, mono-substituted or polysubstituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkyl, aryl or heretoaryl.

4.2.11 General Procedure for the Synthesis of the Intermediates of theCompounds of the Invention

A is an unsubstituted, mono-substituted or polysubstituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl.

4.2.12 General Procedure for the Synthesis of the Intermediates of theCompounds of the Invention

4.2.13 General Procedure for the Synthesis of the Intermediates of theCompounds of the Invention

A is an unsubstituted, mono-substituted or polysubstituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl.

Both enantiomers of the epoxide starting material are available. Thereaction proceeds with inversion at the chiral center.

4.2.14 General Procedure for the Synthesis of the Intermediates of theCompounds of the Invention

A is an unsubstituted, mono-substituted or polysubstituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl.

4.2.15 General Procedure for the Synthesis of the Phenol Intermediatesof the Compounds of the Invention

The phenols that are not commercial products were synthesized byapplication of methodology known in the art and routes outlined below.

Synthesis of Sesamol-Derivatives

4.2.16 Procedure for the Synthesis of 3-aryloxy, 3-arythio and3-arylamino-2-propanolamines Method A

A 20 mL microwaveable vial was charged withN-(2,3-epoxypropyl)-2-phthalimide (677 mg, 3.0 mmole), the appropriatephenol, thiol or aniline (1.2 equiv, 3.6 mmole), chlorobenzene (10 mL),and 1,8-diazabicyclo[5.4.0]undec-7-ene (100 uL). The vial was sealed andheated under microwaves to 220° C. for 0.5 h. Upon cooling hydrazine(0.189 mL, 6.0 mmol) was added to the reaction vessel. The vial wasre-sealed and heated to 150° C. under microwaves for 12 min. Uponcooling the resulting suspension was poured onto ethyl acetate (100 mL)and extracted twice with 0.5 N NaOH (50 mL/extraction). The ethylacetate fraction was isolated and extracted with saturated aqueoussodium chloride (25 mL). The ethyl acetate layer was isolated and driedover magnesium sulfate. The solid was removed by filtration and thevolatiles were removed from the filtrate in vacuo to afford the product.

4.2.16.1 Compounds Prepared by Method A

Specific embodiments of compounds of formula (1) include, but are notlimited to the following compounds that were prepared according tomethod A described above (Table I):

TABLE I Molecular Structure Formula [M + H]⁺ H NMR

C9H12FNO2 186.2 (CDCl₃): δ 7.10-7.30 (m,1H, overlapped), 6.55-6.75 (m,3H), 3.90-4.00.(m, 3H), 2.85-3.05 (m,2H).

C10H15NO2S 214.3 (DMSO-d₆): δ 7.18-7.23(m, 1H), 6.87-6.89 (m,2H),6.71-6.74. (m, 1H),4.98 (bs, 1H), 3.80 (s,3H), 3.48-3.52 (m,1H),3.05-3.11 (m, 1H), 2.87-2.94 (m, 1H), 2.50-2.70(m, 2H, overlapped),1.48(brs, 2H).

C12H17ClN2O 241.7 (CD₃OD): δ 6.79-6.85 (m,2H), 6.40-6.42 (m,1H),3.78-3.87 (m, 1H), 3.29-3.39 (m, 2H), 2.62-3.08(m, 6H), 1.37 (s,3H).

C10H12N2O2 193.2

C12H17NO2 208.3

C9H12N2O4 213.2

C9H8F5NO2 258.2

C9H11Cl2NO2 237.1

C10H14FNO2 200.2

C9H11BrFNO2 265.1

C10H14N2O4 227.2

C10H14N2O4 227.2

C10H10ClF4NO2 288.6

C10H11ClF3NO3 286.7

C10H12F3NO2S 268.3

C11H16N2O4 241.3

C9H11Cl2NO2 237.1

C11H13F4NO3 284.2

C10H11ClN2O2 227.7

C17H27NO3 294.4

C15H17N3O2 272.3

C14H18N2O2 247.3

C10H12F3NO2 236.2

C10H15NO2S 214.3

C10H13NO4 212.2

C9H12N2O4 213.2

C9H12FNO2 186.2

C10H14INO2 308.1

C9H11F2NO2 204.2

C9H12BrNO2 247.1

C10H12F3NO3 252.2

C13H21NO2 224.3

C10H14BrNO3 277.1

C9H11Cl2NO2 237.1

C9H11ClFNO2 220.6

C9H11Cl2NO2 237.1

C9H11Cl2NO2 237.1

C10H14ClNO2 216.7

C9H10ClF2NO2 238.6

C13H15NO2 218.3

C15H17NO2 244.3

C13H15NO2 218.3

C10H14ClNO2 216.7

C14H17NO3 248.3

C14H17NO3 248.3

C15H25NO4 284.4

C14H17NO2 232.3

C11H17NO4 228.3

C10H14ClNO3 232.7

C11H16ClNO2 230.7

C12H19NO5 258.3

C11HI7NO4 228.3

C15H17NO2 244.3

C13H21NO3 240.3

C10H14FNO2 200.2

C15H17NO2 244.3

C15H16ClNO2 278.8

C16H19NO3 274.3

C15H17NO3 260.3

C15H16FNO2 262.3

C11H17NO4 228.3

C15H16N2O2 257.3

C15H16N2O2 257.3

C16H16N2O2 269.3

C15H22N2O2 263.4

C10H11ClN2O2 227.7

C16H16N2O2 269.3

C16H16N2O2 269.3

C16H16N2O2 269.3

C11H17NO4 228.3

C11H16ClNO2 230.7

C10H13ClFNO2 234.7

C14H21NO4 268.3

C15H25NO2 252.4

C11H17NO2 196.3

C10H14ClNO2 216.7

C11H17NO2 196.3

C14H23NO2 238.3

C11H17NO2 196.3

C10H15NO2 182.2

C13H21NO2 224.3

C10H15NO2 182.2

C10H13F2NO2 218.2

C12H19NO4 242.3

C14H23NO2 238.3

C14H23NO2 238.3

C9H12ClNO2 202.7

C9H9Cl2FNO 236.9

C11H17NO2 196.3

C13H20N2O3 253.3

C15H21NO4 280.3

C12H16N2O2 221.3

C11H18N2O2 211.3

C12H19NO2 210.3

C10H13ClFNO2 234.7

C12H19NO2 210.3

C14H23NO2 238.3

C11H14Cl2NO2 267.9

C11H14N2O3 223.2

C11H17NO2 196.3

C11H17NO2 196.3

C10H15NO2 182.2

C13H16N2O2 233.3

C11H17NO2 196.3

C9H11ClFNO2 220.6

C12H19NO2 210.3

C13H20ClNO2 258.8

C12H16N2O2 221.3

C13H19NO3 238.3

C10H14ClNO2 216.7

C13H20NO2 223.4

C10H14FNO2 200.2

C10H11FN2O2 211.2

C10H14FNO2 200.2

C13H21NO2 224.3

C11H14N2O2S 239.3

C13H19NO2 222.3

C10H14ClNO2 216.7

C11H16ClNO2 230.7

C13H21NO3 240.3

C11H17NO2S 228.3

C10H14ClNO2 216.7

C10H14FNO2 200.2

C13H20N2O2 237.3

C10H12F3NO2S 268.3

C10H13C12NO2 251.1

C10H14N2O4 227.2

C10H14N2O4 227.2

C10H15NO2S 214.3

C9H12ClNOS 218.7

C10H15NO2S 214.3

C10H15NOS 198.3

C9H12ClNOS 218.7

C10H15NOS 198.3

C10H15NOS 198.3

C10H15NO2S 214.3

C9H13ClN2O 201.7

C12H17ClN2O 241.7

C11H16BrNO2 275.2

C14H14N2O2 243.3

C11H17NO2 196.3

C9H12ClNO2 202.7

C12H19NO2 210.3

C9H11C12NO2 237.1

C10H11BrN2O2 272.1

C11H16ClNO2 230.7

C10H14ClNO2 216.7

C10H12N2O2 193.2

C13H20N2O3 253.3

C10H11ClN2O2 227.7

C16H19NO3 274.3

C9H11C12NO2 237.1

C9H12ClNOS 218.7

4.2.17 Procedure for synthesis of2-{4-[2-hydroxy-3-aryloxypropyl)amino]-2-oxo-1,2-dihydropyridin-3-yl]-6-(methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-diones,2-{4-[2-hydroxy-3-arylthiopropyl)amino]-2-oxo-1,2-dihydropyridin-3-yl}-6-(methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-diones,and2-{4-[2-hydroxy-3-arylaminopropyl)amino]-2-oxo-1,2-dihydropyridin-3-yl}-6-(methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionesMethod B

An array of 8 mL vials, each containing one of the propanolaminesprepared by Method A (100 umol), was prepared. A 0.1 M stock solution of2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionein 15% triethylamine in ethyl acetate (v/v) was prepared. To each of thevials was added the template stock solution (1000 uL, 1.0 equiv). Thevials were capped and heated to 100° C. for 16 h. Upon cooling thevolatiles were removed in vacuo and the resultant residue was purifiedby HPLC.

4.2.17.1 Compounds Prepared by Method B

Specific embodiments of compounds of formula (1) include, but are notlimited to the following compounds that were prepared according tomethod B described above (Table II):

TABLE II Molecular Structure Formula [M + H]⁺

C29H29FN6O5 561.6

C30H29N7O5 568.6

C32H34N6O5 583.7

C29H29N7O7 588.6

C29H25F5N6O5 633.5

C29H28Cl2N6O5 612.5

C30H31FN6O5 575.6

C29H28BrFN6O5 640.5

C30H31N7O7 602.6

C30H31N7O7 602.6

C30H27ClF4N6O5 664.0

C30H28ClF3N6O6 662.0

C30H29F3N6O5S 643.7

C31H33N7O7 616.6

C31H30F4N6O6 659.6

C37H44N6O6 669.8

C35H34N8O5 647.7

C30H29F3N6O5 611.6

C30H32N6O5S 589.7

C30H30N6O7 587.6

C29H29N7O7 588.6

C29H29FN6O5 561.6

C30H31IN6O5 683.5

C29H28F2N6O5 579.6

C29H29BrN6O5 622.5

C30H29F3N6O6 627.6

C33H38N6O5 599.7

C30H31BrN6O6 652.5

C29H28Cl2N6O5 612.5

C29H28ClFN6O5 596.0

C29H28Cl2N6O5 612.5

C29H28Cl2N6O5 612.5

C30H31ClN6O5 592.1

C29H27ClF2N6O5 614.0

C33H32N6O5 593.7

C35H34N6O5 619.7

C33H32N6O5 593.7

C30H31ClN6O5 592.1

C34H34N6O6 623.7

C34H34N6O6 623.7

C35H42N6O7 659.8

C34H34N6O5 607.7

C31H34N6O7 603.6

C30H31ClN6O6 608.1

C31H33ClN6O5 606.1

C32H36N6O8 633.7

C31H34N6O7 603.6

C35H34N6O5 619.7

C33H38N6O6 615.7

C35H34N6O5 619.7

C35H33ClN6O5 654.1

C36H36N6O6 649.7

C35H34N6O6 635.7

C35H33FN6O5 637.7

C31H34N6O7 603.6

C35H33N7O5 632.7

C35H33N7O5 632.7

C31H33ClN6O5 606.1

C30H30ClFN6O5 610.1

C34H38N6O7 643.7

C35H42N6O5 627.8

C31H34N6O5 571.7

C30H31ClN6O5 592.1

C31H34N6O5 571.7

C34H40N6O5 613.7

C31H34N6O5 571.7

C30H32N6O5 557.6

C33H38N6O5 599.7

C30H32N6O5 557.6

C30H30F2N6O5 593.6

C32H36N6O7 617.7

C34H40N6O5 613.7

C34H40N6O5 613.7

C29H29ClN6O5 578.0

C31H34N6O5 571.7

C33H37N7O6 628.7

C35H38N6O7 655.7

C32H33N7O5 596.7

C31H35N7O5 586.7

C32H36N6O5 585.7

C30H30ClFN6O5 610.1

C32H36N6O5 585.7

C34H40N6O5 613.7

C31H34N6O5 571.7

C31H34N6O5 571.7

C30H32N6O5 557.6

C33H33N7O5 608.7

C31H34N6O5 571.7

C29H28ClFN6O5 596.0

C32H36N6O5 585.7

C33H37ClN6O5 634.2

C32H33N7O5 596.7

C33H36N6O6 613.7

C30H31ClN6O5 592.1

C30H31FN6O5 575.6

C33H38N6O5 599.7

C33H36N6O5 597.7

C30H31ClN6O5 592.1

C31H33ClN6O5 606.1

C33H38N6O6 615.7

C30H31ClN6O5 592.1

C30H31FN6O5 575.6

C30H29F3N6O5S 643.7

C30H30Cl2N6O5 626.5

C30H32N6O5S 589.7

C30H32N6O5S 589.7

C30H32N6O4S 573.7

C29H29ClN6O4S 594.1

C30H32N6O4S 573.7

C29H30ClN7O4 577.1

C32H35N7O4 582.7

4.3 Methods of Use

In one aspect, provided are methods for modulating the activity of atyrosine kinase. In general, the methods comprise the step of contactingthe tyrosine kinase with a compound of the invention. The contacting canbe in any environ known to those of skill in the art, for instance, invitro, in vivo, ex vivo or otherwise. In certain embodiments, thepresent invention provides methods of modulating the activity of atyrosine kinase in a mammal in need thereof comprising contacting thetyrosine kinase with a compound of the invention.

In another aspect, the protein tyrosine kinase, the catalytic activityof which is modulated by contact with a compound provided herein, or astereoisomer, tautomer, salt, hydrate or prodrug thereof, is a receptorprotein tyrosine kinase (RTK). Among the receptor protein tyrosinekinases whose catalytic activity can be modulated with a compound ofthis invention, are, without limitation, Alk, Axl, CSFR, DDR1, DDR2,EphB4, EphA2, EGFR, Flt-1, Flt3, Flt4, FGFR1, FGFR2, FGFR3, FGFR4, HER2,HER3, HER4, IR, IGF1R, IRR, Kit, KDR/Flk-1, Met, Mer, PDGFR.alpha.,PDGFR.beta., Ret, Ros, Ron, Tie1, Tie2, TrkA, TrkB, TrkC.

In yet another aspect, the protein tyrosine kinase whose catalyticactivity is modulated by contact with a compound of this invention, or astereoisomer, tautomer, salt, hydrate or prodrug thereof, can also be anon-receptor or cellular protein tyrosine kinase (CTK). Thus, thecatalytic activity of CTKs such as, without limitation, Abl, Arg, Ack,Blk, Bmx, Brk, Btk, Csk, Fak, Fes, Fgr, Fps, Frk, Fyn, Hck, Itk, Jak1,Jak2, Jak3, Lck, Lyn, Src, Syk, Tec, Yes, ZAP70, may be modulated bycontact with a compound or a stereoisomer, tautomer, salt, hydrate orprodrug thereof provided herein.

In another aspect, provided are methods for treating or preventing atyrosine kinase related disorder in a subject in need thereof. Ingeneral, the methods comprise administering to the subject an amount ofa compound or a stereoisomer, tautomer, salt, hydrate or prodrug thereofeffective to treat or prevent the disorder. The compound can be in theform of a pharmaceutical composition or a unit dose as described below.

A tyrosine kinase related disorder can be any disorder known to those ofskill in the art to be related to tyrosine kinase activity. Suchdisorders include those related to excessive tyrosine kinase active,those related to reduced tyrosine kinase activity and to those that canbe treated or prevented by modulation of tyrosine kinase activity.Excessive tyrosine kinase activity can arise as the result of, forexample: (1) tyrosine kinase expression in cells which normally do notexpress tyrosine kinases; (2) increased tyrosine kinase expressionleading to unwanted cell proliferation, differentiation and/or growth;or, (3) decreased tyrosine kinase expression leading to unwantedreductions in cell proliferation, differentiation and/or growth.

The tyrosine kinase related disorder can be a cancer selected from, butnot limited to, astrocytoma, basal or squamous cell carcinoma, braincancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer,chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma,esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing'ssarcoma, gastrointestinal cancer, head and neck cancer, hepatoma,glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma,non-small cell lung cancer, neural cancer, ovarian cancer, pancreaticcancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, smallcell lung cancer, thyoma, thyroid cancer, testicular cancer andosteosarcoma in a further aspect of this invention.

Other tyrosine kinase related disorder includes an IGFR-related disorderselected from diabetes, an autoimmune disorder, Alzheimer's and othercognitive disorders, a hyperproliferation disorder, aging, cancer,acromegaly, Crohn's disease, endometriosis, diabetic retinopathy,restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis,an inflammatory disorder and angiogenesis.

Other disorders which might be treated with compounds of this inventioninclude, without limitation, immunological and cardiovascular disorderssuch as atherosclerosis.

4.4 Compositions and Method of Administration

In certain aspects, provided herein are compositions comprising acompound or a stereoisomer, tautomer, salt, hydrate or prodrug providedherein. The compositions can be used, for example, in the methods of usedescribed herein.

In certain embodiments, a composition is a pharmaceutical composition ora single unit dosage form. Pharmaceutical compositions and single unitdosage forms comprise a prophylactically or therapeutically effectiveamount of one or more prophylactic or therapeutic agents (e.g., acompound of the invention, or other prophylactic or therapeutic agent),and a typically one or more pharmaceutically acceptable carriers orexcipients or diluents. In one non-limiting embodiment, the term“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans. The term “carrier” refers to a diluent, adjuvant(e.g., Freund's adjuvant (complete and incomplete)), excipient, orvehicle with which the therapeutic is administered. Such pharmaceuticalcarriers can be sterile liquids, such as water and oils, including thoseof petroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water is a particularcarrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Examples of suitable pharmaceutical carriers aredescribed in “Remington's Pharmaceutical Sciences” by E. W. Martin.

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well-known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients include starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. Whether a particular excipient is suitablefor incorporation into a pharmaceutical composition or dosage formdepends on a variety of factors well known in the art including, but notlimited to, the way in which the dosage form will be administered to apatient and the specific active ingredients in the dosage form. Thecomposition or single unit dosage form, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are in certainembodiments anhydrous if substantial contact with moisture and/orhumidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition can be prepared and stored suchthat its anhydrous nature is maintained. Accordingly, anhydrouscompositions are in certain embodiments packaged using materials knownto prevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Further provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, tablets, pills, capsules,powders, sustained-release formulations and the like. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such compositions and dosage forms willcontain a prophylactically or therapeutically effective amount of aprophylactic or therapeutic agent in certain embodiments in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the patient. The formulation shouldsuit the mode of administration. In certain embodiments, thepharmaceutical compositions or single unit dosage forms are sterile andin suitable form for administration to a subject, in certain embodimentsan animal subject, such as a mammalian subject, particularly a humansubject.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,oral, buccal, sublingual, inhalation, intranasal, transdermal, topical,transmucosal, intra-tumoral, intra-synovial and rectal administration.In a specific embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous, subcutaneous, intramuscular, oral, intranasal or topicaladministration to human beings. In an embodiment, a pharmaceuticalcomposition is formulated in accordance with routine procedures forsubcutaneous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocamne to ease pain at the siteof the injection.

Examples of dosage forms include, but are not limited to: tablets;caplets; capsules, such as soft elastic gelatin capsules; cachets;troches; lozenges; dispersions; suppositories; ointments; cataplasms(poultices); pastes; powders; dressings; creams; plasters; solutions;patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosageforms suitable for oral or mucosal administration to a patient,including suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disorder may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Also, the therapeutically effective dosage form may vary among differenttypes of cancer. Similarly, a parenteral dosage form may contain smalleramounts of one or more of the active ingredients it comprises than anoral dosage form used to treat the same disease or disorder. These andother ways in which specific dosage forms encompassed by this inventionwill vary from one another will be readily apparent to those skilled inthe art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Generally, the ingredients of compositions of the invention are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the composition is to be administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Typical dosage forms of the invention comprise a compound of theinvention, or a pharmaceutically acceptable salt, solvate or hydratethereof lie within the range of from about 0.1 mg to about 1000 mg perday. Particular dosage forms of the invention have about 0.1, 0.2, 0.3,0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200,250, 500 or 1000 mg of the compound.

4.4.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be presented as discrete dosage forms, such as, but are not limitedto, tablets (e.g., chewable tablets), caplets, capsules, and liquids(e.g., flavored syrups). Such dosage forms contain predetermined amountsof active ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

In certain embodiments, the oral dosage forms are solid and preparedunder anhydrous conditions with anhydrous ingredients, as described indetail in the sections above. However, the scope of the inventionextends beyond anhydrous, solid oral dosage forms. As such, furtherforms are described herein.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, PA), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

4.4.2 Controlled Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include, butare not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566,each of which is incorporated herein by reference. Such dosage forms canbe used to provide slow or controlled-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients of the invention. Theinvention thus encompasses single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gelcaps,and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are in certain embodimentssterile or capable of being sterilized prior to administration to apatient. Examples of parenteral dosage forms include, but are notlimited to, solutions ready for injection, dry products ready to bedissolved or suspended in a pharmaceutically acceptable vehicle forinjection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

4.4.4 Transdermal, Topical & Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.4.5 Dosage & Frequency of Administration

The amount of the compound or composition provided herein which will beeffective in the prevention, treatment, management, or amelioration of adisorder or one or more symptoms thereof will vary with the nature andseverity of the disease or condition, and the route by which the activeingredient is administered. The frequency and dosage will also varyaccording to factors specific for each patient depending on the specifictherapy (e.g., therapeutic or prophylactic agents) administered, theseverity of the disorder, disease, or condition, the route ofadministration, as well as age, body, weight, response, and the pastmedical history of the patient. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

Exemplary doses of a compound include milligram or microgram amounts ofthe active peptide per kilogram of subject or sample weight (e.g., about1 microgram per kilogram to about 500 milligrams per kilogram, about 100micrograms per kilogram to about 5 milligrams per kilogram, or about 1microgram per kilogram to about 50 micrograms per kilogram). In general,the recommended daily dose range of a compound of the invention for theconditions described herein lie within the range of from about 0.01 mgto about 1000 mg per day, given as a single once-a-day dose in certainembodiments as divided doses throughout a day. It may be necessary touse dosages of the active ingredient outside the ranges disclosed hereinin some cases, as will be apparent to those of ordinary skill in theart. Furthermore, it is noted that the clinician or treating physicianwill know how and when to interrupt, adjust, or terminate therapy inconjunction with individual patient response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compoundsof the invention are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a patient isadministered multiple dosages of a compound of the invention, not all ofthe dosages need be the same. For example, the dosage administered tothe patient may be increased to improve the prophylactic or therapeuticeffect of the compound or it may be decreased to reduce one or more sideeffects that a particular patient is experiencing.

In certain embodiments, administration of the same compound may berepeated and the administrations may be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, or 6 months. In other embodiments, administration of thesame prophylactic or therapeutic agent may be repeated and theadministration may be separated by at least at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or 6 months.

4.4.6 Biological Assays

The following assays can be employed in ascertaining the activity of asmall-molecule compound as an inhibitor of the catalytic kinase activityof various tyrosine kinases.

4.4.6.1 Kinase Assays

To determine inhibition of several tyrosine kinases, such as IGF1R,InsR, Alk, TrkA and Jak2, kinase assays are conducted using eitherKinase-Glo (Promega) or AlphaScreen (PerkinElmer) kinase assayplatforms. The Kinase-Glo Luminescent Kinase Assay is a homogeneousmethod for measuring kinase activity by determining the amount of ATPremaining after a kinase reaction. The luminescent signal isproportional to the amount of ATP and inversely proportional to theamount of kinase activity. Tyrosine kinase PT66 AlphaScreen Assay is ahigh-sensitivity homogeneous, anti-phosphotyrosine antibody-mediatedluminescent proximity method measuring, incorporation of phosphate insynthetic poly(Glu-Tyr) substrate. The kinase preparations used consistof purified recombinant, 6×His- or GST-tagged kinase domain fragments ofthe corresponding RTKs expressed in baculovirus system.

4.4.6.1.1 ELISA-Based Assay of IGF1 Receptor AutophosphorylationInhibition in Cells

In another embodiment, compounds that interact with the IGF1R kinasedomain are tested in a cell-based assay system. In accordance with thisembodiment, cells expressing a full-length IGF1 receptor or a fragmentthereof containing the IGF1R kinase domain, are contacted with acandidate or a control compound and the ability of the compound to blocktyrosine kinase activity of IGF1R within a cell is determined. Thisassay may be used to screen a single compound or a large library ofcandidate compounds. Typically, the cells or cell lines are of mammalianorigin and they can express the IGF1 receptor, or functional IGF1Rkinase domain fragment, endogenously or be genetically engineered toexpress the IGF1R, or functional fragment thereof. The ability of thecandidate compound to inhibit IGF1R kinase activity can be determined bymethods known to those skilled in the art. For example, the inhibitioncan be determined by ELISA-type assay or Western blot analysis with celllysates or immunoprecipitated IGF1R receptor using various anti-IGF1Rand anti-phosphotyrosine antibodies.

In general, cells expressing IGF1R are treated with modulators (i.e.,inhibitors or activators) of IGF1R kinase activity and cell lysates areproduced from these treated cells. IGF1Rs are isolated from the lysateby immunoprecipitation and analyzed for phosphotyrosine content.Alternatively, or in addition, cellular protein substratesphosphorylated by IGFR may be immunoprecipitated from the lysates andtheir degree of tyrosine phosphorylation determined.

4.4.6.2 Cell Proliferation Inhibition Assay

IGF1R and other tyrosine kinase inhibitors can inhibit the proliferationof certain cancer cell lines indicating their possible therapeuticutility for treating the corresponding cancer types. Cancer cell linesof interest and control normal lines, including CHO, HEK293, BA/F3, MM1,H929, COLO205, PC3, DU145, MCF7, Panc1, ACHN, Hep G2, H460, K562, TT,U87-G, CAOV-3, SK-MEL5, Karpas 299, are plated in white, clear-bottomed384-well cell culture plates at 2500-5000 cells per well and suppliedwith dilutions of tested compounds After a desired period of time(typically 3 days), the number of viable cells is quantitated by usingCell Titer-Glo Luminescent Cell Viability Assay (Promega), a cellproliferation assay system based on detection of total amount of ATPpresent as a measure of cell metabolic activity. The plated cells aremixed with the Cell Titer-Glo developing reagent and counted in aluminescence multiwell plate reader according to the standardmanufacturer's protocol to generate IC50 curves for cell proliferationinhibition.

4.4.6.3 Kinase Profiling

To determine inhibitory activity of the compounds against a panel oftyrosine and serine-threonine kinases, the commercial kinase panelprofiling service (Kinase Profiler, Upstate Biotechnologies) isutilized. This kinase inhibition profiling platform consists of standardradiometric kinase assays in filter binding format based on directmeasurements of radioactive phosphate incorporation in specific kinasesubstrates by scintillation counting.

The disclosure is further described by the way of non-limiting examples.

5. EXAMPLES 5.1 Example 1 Synthesis of the Compounds According ToFormula (1) 5-Amino-6-nitro-isoindole-1,3-dione

Synthesis of 5-Amino-6-nitro-isoindole-1,3-dione(4-nitro-5-aminophthalimide) from 5-chloro-6-nitroisoindoline-1,3-dione(4-chloro-5-nitrophthalimide) is described in the following: ApplicationNo. CN 1314350 A20010926 and CN 2001-111559, 20010323.

The following procedure is our modification: A mixture of5-chloro-6-nitroisoindoline-1,3-dione (28.0 g, 0.123 mol) and urea (73.8g, 1.23 mol) was stirred at 150° C. for 6 h. Then the temperature wasreduced to 90° C., water (400 mL) was added, the mixture was stirredovernight at RT. Precipitate was collected by filtration, water (300 mL)was added and stirred for 4 h at 95° C. The solid was collected byfiltration and dried under vacuum. Yellow solid, 19.6 g (94.7 mmol,77%). LCMS [M−H]-205.9. ¹H NMR (300 MHz, DMSO): δ 11.46 (s, 1H), 8.35(s, 2H), 8.37 (s, 1H), 7.40 (s, 1H).

N-Substituted Phthalimides (2-substituted5-chloro-6-nitroisoindoline-1,3-diones

General Procedure A: A mixture of 5-amino-6-nitro-isoindole-1,3-dione 1(207 mg, 1.0 mmol), amine 2 (1.0 mmol) and diphenyl ether (3 mL) wasstirred overnight under nitrogen at 210° C., then cooled to 50° C.,diluted with hexane. Precipitate was collected by filtration.

General Procedure B: A mixture of 5-amino-6-nitro-isoindole-1,3-dione 1(12.84 g, 62.0 mmol), amine 2 (62.0 mmol), imidazole (4.22 g, 62.0 mmol)and diphenyl ether (50 mL) was stirred for 5 h under N₂ at 170° C. Thenthe reaction mixture was cooled to RT, ethanol (500 mL) was added, themixture was refluxed for 1 h. After cooling to −20° C. yellowprecipitate was collected by filtration, washed with cold ethanol anddried in vacuum at 100° C. overnight.

General Procedure C: A suspension of phthalimide 1 (292 mg, 1.41 mmol),diethylcarbonate (179 mg, 151 mmol) in 1,4-dioxane (3 mL), to which wasthen added DBU (0.217 ml, 1.45 mmol), was heated at 90-95° C. for 15min. The amine 2 (1.44 mM) was then added and the reaction suspensionwas stirred at 100° C. for approximately 30 min at which point a darksolution had resulted. The reaction was cooled to room temperature andevaporated to reddish foam under reduced pressure. Ethanol (3 mL) wasthen added and a yellow suspension formed. The yellow solid was isolatedvia filtration and washed with ethanol, then dried in vacuum overnightto afford the product 3.

General Procedure D: To a suspension of substituted phthalimide indioxane (1-200-fold volume [mL]/weight [g] based on the phthalimidederivative, preferably 5-20 mL of 1,4-dioxane per g of the phthalimidederivative) is added equimolar amount of the amine R′—NH₂, imidazole(between 0.01% to 100% of the molar equivalent of the phthalimide[isoindoline-1,3-dione]) and heated to between 100° C. to 200° C.,preferably to between 110° C. to 150° C., when necessary in a closedpressure vessel with efficient agitation. Then the reaction mixture iscooled to RT and diluted with hexane. The product is filtered by suctionand washed with a small amount of cold ether or other suitable solvent.Alternatively the mixture is concentrated in vacuo and the product maybe further purified by washing with ether, hexane or ethyl acetate ortheir mixture. The product can also be purified by recrystallizationfrom alcohol, or isopropanol. The product can also be purified byacid-base extraction, column chromatography, or HPLC.

5-Amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione wasprepared by General procedure B. Yield 74%. LCMS: [M+H]⁺ 305.4

¹H NMR: (300 MHz, DMSO) δ 8.38 (s, 2H), 8.28 (s, 1H), 7.41 (s, 1H), 3.89(m, 1H), 2.85 (d, J=11.3 Hz, 2H), 2.30 (m, 2H), 2.18 (s, 3H), 1.92 (t,J=11.3 Hz, 2H), 1.58 (d, J=10.9 Hz, 2H).

5-Amino-2-[2-(1H-imidazol-4-yl)-ethyl]-6-nitro-isoindole-1,3-dione wasprepared by General procedure A. The product was additionally purifiedby chromatography on SiO₂ (CHCl₃-MeOH—NH₄OH 100:10:1). Yield 224 mg(0.74 mmol, 74%). LCMS [M+H]⁺ 302.4.

¹H NMR (300 MHz, DMSO): δ 11.81 (s, 1H), 8.40 (s, 2H), 2.30 (s, 1H),7.48 (s, 1H), 7.43 (s, 1H) 6.81 (s, 1H), 3.75 (m, 2H), 2.79 (m, 2H).

5-Amino-6-nitro-2-(3-pyrrolidin-1-yl-propyl)-isoindole-1,3-dione wasprepared by General procedure A. The product was additionally purifiedby reverse phase chromatography (CH₃CN—H₂O-TFA). Yield 60 mg (0.19 mmol,19%). LCMS [M+H]⁺ 319.4.

¹H NMR (300 MHz, CDCl₃): δ 8.55 (s, 1H), 7.40 (s, 2H), 3.80 (m, 2H),3.22 (m, 2H), 2.85 (m, 2H), 2.00-2.20 (6H), 1.60 (br. s., 4H).

5-Amino-2-(3-morpholin-4-yl-propyl)-6-nitro-isoindole-1,3-dione wasprepared by General procedure A. The product was additionally purifiedby reverse phase chromatography (CH₃CN—H₂O-TFA). Yield 149 mg (0.45mmol, 45%). LCMS: [M+H]⁺ 335.5

¹H NMR (300 MHz, DMSO): δ 8.40 (s, 2H), 8.31 (s, 1H), 7.45 (s, 1H), 3.60(m, 2H), 3.41 (m, 4H), 2.26 (m, 6H), 1.72 (m, 2H).

5-Amino-2-[3-(4-methyl-piperazin-1-yl)-propyl]-6-nitro-isoindole-1,3-dionewas prepared by General procedure A. The product was additionallypurified by RP chromatography (CH₃CN—H₂O-TFA). Yield 110 mg (0.32 mmol,32%). LCMS: [M+H]⁺ 348.3

¹H NMR (300 MHz, DMSO): δ 8.44 (s, 2H), 8.32 (s, 1H), 7.47 (s, 1H), 3.60(m, 2h), 3.50-2.70 (13H), 1.85 (m, 2H).

5-Amino-2-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-6-nitro-isoindole-1,3-dionewas prepared by General procedure A. Yield 270 mg (0.77 mmol, 77%). LCMS[M+H]⁺ 349.3

¹H NMR (300 MHz, DMSO): δ 8.39 (s, 2H), 8.30 (s, 1H), 7.45 (s, 1H), 4.33(m, 1H), 3.43 (m, 4H), 2.81 (m, 2H), 2.35 (m, 2H), 1.87 (m, 2H), 1.55(m, 3H), 1.15 (m, 2H).

5-Amino-2-[1-(2-methoxy-ethyl)-piperidin-4-ylmethyl]-6-nitro-isoindole-1,3-dionewas prepared by General procedure B “Imidazole”. Yield 267 mg (0.74mmol, 74%). LCMS [M+H]⁺ 363.5

¹H NMR (300 MHz, DMSO): δ 8.41 (s, 2H), 8.31 (s, 1H), 7.45 (s, 1H), 3.38(m, 4H), 3.21 (s, 3H), 2.80 (m, 2H), 2.40 (m, 2H), 1.85 (m, 2H), 1.60(m, 1H), 1.54 (m, 2H), 1.24 (m, 2H).

5-Amino-2-(3-hydroxy-2,2-dimethyl-propyl)-6-nitro-isoindole-1,3-dionewas prepared by General procedure B “Imidazole”. Yield 168 mg (0.57mmol, 57%).

LCMS [M−H]-292.3

¹H NMR (300 MHz, DMSO): δ 8.40 (s, 2H), 8.32 (s, 1H), 7.45 (s, 1H), 4.58(t, J=5.5 Hz, 1H), 3.45 (s, 2H), 3.16 (d, J=5.5 Hz, 2H), 0.80 (s, 6H).

5-Amino-2-(2-hydroxy-1-hydroxymethyl-ethyl)-6-nitro-isoindole-1,3-dionewas prepared by General procedure B “Imidazole”. Yield 271 mg (0.96mmol, 96%).

LCMS [M−H]-279.8

¹H NMR (300 MHz, DMSO): δ 8.39 (s, 2H), 8.30 (s, 1H), 7.44 (s, 1H), 4.85(m, 2H), 4.20 (m, 1H), 3.78 (m, 2H), 3.63 (m, 2H).

5-Amino-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-6-nitro-isoindole-1,3-dionewas prepared by General procedure C “diethylcarbonate”. Yield 140 mg(0.42 mmol, 42%) LCMS [M+H]⁺ 334.5

¹H NMR (300 MHz, DMSO): δ 8.59 (s, 2H), 8.40 (s, 1H), 7.45 (s, 1H), 3.65(m, 2H), 2.20-2-10 (m, 10H), 2.10 (s, 3H).

Aminoalcohols

Procedure for the Synthesis of Optically Active aminoalcohol(S)-2-(3-chlorophenyl)-2-hydroxy-ethylamine

(S)—1-(3-Chlorophenyl)-ethane-1,2-diol: AD mix alpha (86.0 g) was addedto a stirred mixture of tert-BuOH (300 mL) and H₂O (300 mL), mixture wasstirred for 15 min at RT, than cooled to 0° C. 3-Chlorostyrene (8.51 g,0.061 mol) was added over 15 min and the mixture was stirred at 0° C.for 48 h. The reaction mixture was quenched by adding 10% aq. sodiumsulfite (120 mL) followed by addition of EtOAc (200 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (200 mL). Thecombined organic layers were washed with 0.4 M H₂SO₄ in saturated Na₂SO₄(100 mL), followed by drying over Na₂SO₄. The solvent was evaporated andthe residue was separated on SiO₂ (70 g) (CHCl₃-MeOH 0 to 10%).Colorless oil, 9.83 g (0.057 mol, 93%).

¹H NMR (300 MHz, DMSO): δ 7.20-7.40 (m, 4H), 5.39 (d, J=4.6 Hz, 1H),4.76 (t, J=5.8 Hz, 1H), 4.54 (q, J=4.9 Hz, 1H), 3.43 (m, 2H).

Toluene-4-sulfonic acid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester: Toa mixture of (S)-1-(3-Chloro-phenyl)-ethane-1,2-diol (9.83 g, 0.057 mol)and triethylamine (11.8 ml, 0.086 mol) a solution of TsCl (10.87 g,0.057 mol) in dichloromethane (50 mL) was added at 0° C. over 30 min.The mixture was stirred at 0° C. for 4 h. Precipitate formed was removedby filtration, the filtrate was washed with water (50 mL), dried overNa₂SO₄ and evaporated. The residue was dissolved in CH₂Cl₂ (200 mL),filtered through a SiO₂ pad and evaporated. Colorless oil, 16.34 g(0.050 mol, 88%).

¹H NMR (300 MHz, DMSO): δ 7.67 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz,2H), 7.20-7.35 (m, 4H), 5.90 (d, J=4.9 Hz, 1H), 4.79 (q, J=5.1 Hz, 1H),4.03 (m, 2H), 2.41 (s, 3H).

(S)-2-Azido-1-(3-chlorophenyl)-ethanol: A mixture of toluene-4-sulfonicacid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester (16.34 g, 0.050 mol),sodium azide (6.50 g, 0.10 mol) and DMSO (50 mL) was stirred for 2 h at80° C. Water (100 mL) was added, extracted with hexane-ether (1:1)mixture (2×150 mL). Combined extract was dried over Na₂SO₄, evaporated.The residue was separated on SiO₂ (100 g), hexane-EtOAc, 0 to 20%.Colorless oil, 7.0 g, (0.035 mol, 71%).

¹H NMR (300 MHz, DMSO): δ 7.46 (s, 1H), 7.36 (m, 3H), 5.95 (d, J=4.5 Hz,1H), 4.82 (q, J=5.3 Hz, 1H), 3.35 (m, 2H).

(S)-2-Amino-1-(3-chloro-phenyl)-ethanol: A mixture of(S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH₄ (1.97g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for24 h. The solvent was evaporated, the residue was separated on SiO₂ (15g) CHCl₃-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). Thematerial was reacted with Boc₂O in dichloromethane and NEt₃ and analyzedby chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined tobe 91% ee.

LCMS [M+H]⁺ 172.4

¹H NMR (300 MHz, DMSO): δ 7.24-7.39 (m, 4H), 4.46 (dd, J=4.3, 7.5 Hz,1H), 2.68 (dd, J=4.3, 12.8 Hz, 1H), 2.57 (dd, J=7.5, 13.0 Hz, 1H).

(R)-1-Azido-3-(4-fluoro-phenoxy)-propan-2-ol. A mixture of(S)-1-Chloro-3-(4-fluoro-phenoxy)-propan-2-ol (5.0 g, 24.5 mmol), sodiumazide (3.19 g, 49.0 mmol) and DMSO (25 mL) was stirred at 80° C. for 6h. Then the reaction mixture was poured into water (100 mL), extractedwith hexane-Et₂O (1:1) mixture (2×100 mL). Extracts were washed withbrine (100 mL), dried over Na₂SO₄ and evaporated. The residue was driedunder vacuum at RT. Colorless oil, 4.83 g (22.9 mmol, 93%).

¹H NMR (300 MHz, CDCl₃): δ 6.98 (m, 2H), 6.84 (m, 2H), 4.15 (m, 1H),3.97 (m, 2H), 3.52 (m, 2H), 2.57 (d, J=5 Hz, 1H).

(S)-1-Azido-3-(4-fluoro-phenoxy)-propan-2-ol was prepared by the sameprocedure.

(R)-1-Amino-3-(4-fluoro-phenoxy)-propan-2-ol. A mixture of(R)-1-azido-3-(4-fluoro-phenoxy)-propan-2-ol (4.83 g, 22.9 mmol) NaBH₄(1.73 g, 45.8 mmol) in iPrOH (100 mL) was stirred at 80° C. for 24 h.After cooling to RT, aq. HCl (200 mL, 0.25 M) was added, washed withCH₂Cl₂ (100 mL). Saturated aq. K₂CO₃ (150 mL) was added to the aqueousphase. The product was extracted with CH₂Cl₂ (2×100 mL), extracts weredried over Na₂SO₄ and evaporated. The residue was dried under vacuum.White solid, 2.20 g (11.9 mmol, 52%).

LCMS [M+H]⁺ 186.1

¹H NMR (300 MHz, DMSO): δ 7.00 (m, 2H), 6.86 (m, 2H), 3.93 (m, 3H), 2.96(m, 1H), 2.86 (m, 1H), 1.71 (br. s, 3H).

(S)-1-Amino-3-(4-fluoro-phenoxy)-propan-2-ol was prepared by the sameprocedure.

General procedure for preparation of (R)-1-amino-3-aryloxy-propan-2-ols.A mixture of (R)—N-(2,3-epoxypropyl)-phthalimide (1.02 g, 5.0 mmol),phenol (5.0 mmol), p-xylene (2 mL) and DBU (0.05 mL) was stirred underN₂ at 120° C. for 8 h. After cooling to 80° C. ^(i)PrOH (20 mL) andanhydrous hydrazine (1 mL) were added and the mixture was heated at 80°C. for 4 h. The reaction mixture was cooled to RT, 0.5N aq. NaOH (50 mL)was added, extracted with EtOAc (100 mL). Extract was washed with 0.5Naq. NaOH (50 mL), brine (50 mL), dried over Na₂SO₄ and evaporated. Theresidue was triturated with cold Et₂O, the solid was collected byfiltration, dried in vacuum.

The heteroaryloxy analogs and the thio and amino derivatives of areprepared analogously to the above procedure.

(R)-1-Amino-3-(3-chloro-2-methyl-phenoxy)-propan-2-ol

Tan solid, 0.86 g. LCMS: [M+H]⁺ 216.1

¹H NMR: (300 MHz, DMSO): δ 7.16 (m, 1H), 6.97 (m, 2H), 3.93 (m, 2H),3.73 (m, 1H), 2.66 (m, 2H).

(R)-1-Amino-3-(3-chloro-2,6-difluoro-phenoxy)-propan-2-ol

Tan solid, 1.01 g. LCMS [M+H]⁺ 239.9

¹H NMR (300 MHz, DMSO): δ 7.32 (m, 1H), 7.21 (m, 1H), 4.10 (m, 2H), 3.68(m, 1H), 2.63 (m, 2H).

(R)-1-Amino-3-(3-chloro-2-fluoro-phenoxy)-propan-2-ol

Tan solid, 1.25 g. LCMS [M+H]⁺ 219.8

¹H NMR (300 MHz, DMSO): δ 7.15 (m, 3H), 4.02 (m, 2H), 3.77 (m, 1H), 2.64(m, 2H).

(R)-1-Amino-3-(3-trifluoromethylsulfanyl-phenoxy)-propan-2-ol

Tan solid, 1.11 g. LCMS [M+H]⁺ 267.6

¹H NMR (300 MHz, DMSO): δ 7.46 (m, 1H), 7.24 (m, 3H), 4.04 (m, 1H), 3.90(m, 1H), 3.72 (m, 1H), 2.62 (m, 2H).

(R)-1-Amino-3-(2,4,6-trimethyl-phenoxy)-propan-2-ol

Tan solid, 0.89 g. LCMS [M+H]⁺ 210.1

¹H NMR (300 MHz, DMSO): δ 6.81 (s, 2H), 3.64 (m, 3H), 2.73 (m, 1H), 2.60(m, 1H), 2.18 (s, 9H).

(R)-1-Amino-3-(3-chloro-4-methyl-phenoxy)-propan-2-ol

Tan solid, 0.99 g. LCMS [M+H]⁺ 215.8

¹H NMR (300 MHz, DMSO): δ 7.23 (m, 1H), 7.00 (s, 1H), 6.81 (m, 1H), 3.93(m, 1H, 3.82 (m, 1H), 3.65 (m, 1H), 2.61 (m, 2H), 2.23 (s, 3H).

(R)-1-Amino-3-(2,4-dimethyl-phenylsulfanyl)-propan-2-ol

Off white solid, 0.88 g. LCMS [M+H]⁺ 212.1

¹H NMR (300 MHz, DMSO): δ 7.22 (d, J=8.3 Hz, 1H), 7.01 (m, 2H), 4.95(br. s., 1H), 3.48 (m, 1H), 2.97 (dd, J=5.8, 12.9 Hz, 1H), 2.83 (dd,J=6.7, 12.9 Hz, 1H), 2.58 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H).

(R)-1-Amino-3-(2-tert-butyl-4-methyl-phenoxy)-propan-2-ol

Brown solid, 0.94 g. LCMS [M+H]⁺ 238.1

¹H NMR (300 MHz, DMSO): δ 6.96 (s, 1H), 6.83 (m, 2H), 3.83 (m, 3H), 2.70(m, 2H), 2.21 (s, 3H), 1.33 (s, 9H).

(R)-1-Amino-3-(2,2,3-trifluoro-2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-propan-2-ol

White solid, 0.91 g. LCMS [M+H]⁺ 279.9

¹H NMR (300 MHz, DMSO): δ 7.20-6.70 (m, 4H), 4.04 (m, 1H), 3.94 (m, 1H),3.72 (m, 1H), 2.63 (m, 2H).

(R)-1-Amino-3-(2,3,3-trifluoro-2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-propan-2-ol

Brown solid, 1.06 g. LCMS [M+H]⁺ 279.9

¹H NMR (300 MHz, DMSO): δ 7.13 (m, 1H), 7.04-6.78 (m, 3H), 4.00, (m,2H), 3.74 (m, 1H), 2.63 (m, 2H).

(R)-1-Amino-3-(3-chloro-2,6-dimethyl-phenoxy)-propan-2-ol

Orange solid, 0.59 g (starting from 2.9 mmol of phenol). LCMS [M+H]⁺230.1

¹H NMR (300 MHz, DMSO): δ 7.08 (m, 2H), 3.73 (m, 2H), 3.64 (m, 1H), 2.51(m, 2H), 2.27 (s, 3H), 2.22 (s, 2H).

(R)-1-Amino-3-(3-chloro-2,4-dimethyl-phenoxy)-propan-2-ol

Brown solid, 0.59 g (starting from 2.9 mmol of phenol). LCMS [M+H]⁺230.4

¹H NMR (300 MHz, CDCl₃): δ 7.01 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.4 Hz,1H), 3.96 (m, 3H), 2.95 (m, 2H), 2.31 and 2.29 (two overlapped singlets,6H), 2.20 (br. s, 3H).

(R)-1-Amino-3-(3-chloro-4-methoxy-2-methyl-phenoxy)-propan-2-ol

Tan solid, 0.51 g (starting from 3.0 mmol of phenol).

LCMS [M+H]⁺ 246.1.

¹H NMR (300 MHz, CDCl₃): δ 6.73 (s, 2H), 3.95 (m, 3H), 3.86 (s, 3H),2.95 (m, 2H), 2.31 (s, 3H).

(R)-1-Amino-3-(3-methoxy-2-methyl-phenoxy)-propan-2-ol

Beige solid, 0.40 g. LCMS [M+H]⁺ 212.3.

(R)-1-Amino-3-(2,3-difluoro-4-methyl-phenoxy)-propan-2-ol

White solid, 0.49 g. LCMS [M+H]⁺ 218.1.

(R)-1-Amino-3-(3-fluoro-2-methyl-phenoxy)-propan-2-ol

Brown solid, 0.81 g. LCMS [M+H]⁺ 200.4.

(R)-1-Amino-3-(3-methoxy-2,4-dimethyl-phenoxy)-propan-2-ol

Yellow solid, 0.82 g. LCMS [M+H]⁺ 226.4.

(R)-1-Amino-3-(2-trifluoromethoxy-phenoxy)-propan-2-ol

LCMS [M+H]⁺ 251.9.

(R)-1-Amino-3-(2-methylsulfanyl-phenoxy)-propan-2-ol

LCMS [M+H]⁺ 213.9.

(R)-1-Amino-3-o-tolyloxy-propan-2-ol

LCMS [M+H]⁺ 181.9.

(R)-1-Amino-3-(2-ethyl-phenoxy)-propan-2-ol

LCMS [M+H]⁺ 196.1.

Preparation of (R)-1-Amino-3-(2,4-dimethylphenoxy)propan-2-ol

To a solution of (R)—N-(2,3-epoxypropyl)-phthalimide (3.0 g, 14.8 mmol)and 2,4-dimethylphenol (1.6 g, 13.0 mmol) in toluene (30 mL) was addedDBU (1.3 mmol) and the resulting mixture was heated at 120° C. for 18 h.The reaction mixture was cooled to 75° C., diluted with isopropanol (50mL) and treated with hydrazine (4 mL). After stirring the mixture at 80°C. for 4 h, cooled to room temperature and solvents were evaporated invacuo. The residue was dissolved in aq. NaOH (100 mL, 5 N) and extractedwith chloroform (2×100 mL). The combined organic layer was washed withbrine (100 mL) and dried over Na₂SO₄. The solvent was filtered andevaporated in vacuo to afford the desired product as an off-white solid.Yield: 1.7 g, 59% LCMS [M+H]⁺ 196.1 The product can be recrystallizedfrom isopropyl alcohol.

According to this methodology, many derivatives of the above can beprepared from phenols, their heteroaryl analogs, thiols, amines,alcohols and sulfonamides.

Nitration of 3-Methylphthalic anhydride

Methyl-phthalic anhydride (100.0 g) was placed in 1 L-3-neck flaskequipped with thermometer, addition funnel and long reflux condenser andwas added conc. H₂SO₄ (130 mL). The suspension was heated to 70° C.using oil bath. The oil bath was removed and the fuming nitric acid (43mL) was added dropwise while the temperature was maintained between90-110° C. Once addition was completed, conc. HNO₃ (180 mL) was added ata rate the temperature of the reaction mixture don't exceed 110° C.After the addition was complete, the reaction mixture was heated at 90°C. for 2 h. The reaction mixture was cooled to room temperature and letstand overnight. The suspension was poured into ice-water (1 L) andextracted with EtOAc (2×750 mL). The combined organic layer was washedwith water (1 L), dried over Na₂SO₄, filtered and concentrated in vacuoto afford light yellow solid. The obtained solid was triturated withhexanes (1 L), filtered and dried in vacuo to afford the mixture ofnitro-methyl-phthalic acids as a light yellow solid. Yield: 128.0 g,93%.

Esterification of Mixture of nitro-3-methylphthalic acids

To a stirred solution of mixture of nitro-3-methylphthalic acids (124.0g) in anhydrous MeOH (650 mL) was added conc. H₂SO₄ (40 mL) slowly andthe resulting mixture was heated at reflux for 24 h. The reactionmixture was cooled to room temperature, solvent was evaporated in vacuo.The residue was dissolved in EtOAc (1.2 L), washed with water (1 L),sat. aq. NaHCO₃ (2×600 mL) and water (600 mL). The organic layer wasdried over Na₂SO₄, filtered and evaporated in vacuo to afford themixture of methyl-esters (3) (40.0 g, 29%) as a light yellow syrup whichsolidify on standing. The NaHCO₃ wash acidified with conc. HCl to pH=2,and extracted with EtOAc (1 L). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to afford the by-product mono-ester(3a) (90.0 g, 69%) as an off-white solid.

Hydrogenation of Mixture of Nitro-Esters

To a suspension of nitro-methylphthalic esters (40.0 g) and 10% Pd/C(4.0 g) was added MeOH (400 mL) carefully and evacuated under vacuum.The flask was filled with hydrogen under balloon pressure and stirred atroom temperature for overnight. If the reaction is incomplete, addHCl/ether and continue the reaction. After the reaction was completed,the mixture was filtered through Celite bed, washed with MeOH (2×200mL). The combined filtrate was concentrated in vacuo and the residue wasbasified aq. NaHCO₃ solution. The mixture was extracted with EtOAc(2×500 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toafford the mixture of aminomethylphthalic esters in quantitative yield.

Acetylation of Amino-Methylphthalic Esters

To a solution of amino-methylphthalic esters (34.3 g) in THF was added1.2 eq of Ac₂O (19.0 mL) and the mixture was heated at 50° C. for 6 h.The reaction mixture was evaporated in vacuo and the residue wasneutralized with aq, NaHCO₃ solution. The mixture was extracted withEtOAc (2×400 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto afford a mixture of isomers. The mixture was triturated with ether(300 mL), filtered the precipitated solid, washed with cold ether (2×50mL) and dried to afford 4-acetamido-3-methylphthalic acid dimethyl ester(17.1 g, 40%) as a white solid. The ether layer contains above 90% of6-acetamido-3-methylphthalic acid dimethyl ester.

¹H NMR (CDCl₃, 300 MHz) for compound 6: δ 2.16 (s, 3H); 2.22 (s, 3H);3.88 (s, 3H); 3.97 (s, 3H); 7.37 (br. s, 1H); 7.83 (d, J=6.0 Hz, 1H);8.03 (d, J=6.0 Hz, 1H). ESI-MS (m/z): 266 (M+H⁺); 234 (M−32).

Synthesis of 4-Acetylamido-3-methyl-5-nitro-phthalic acid dimethyl ester

To a cold solution of fuming HNO₃ was added compound 6 (2.44 g, 9.20mmol) in portions at 0° C. and the mixture was kept standing at 4° C.for overnight. The reaction mixture was poured into ice-water (200 mL)and extracted with EtOAc (2×200 mL). The combined organic layer waswashed with aq. NaHCO₃ solution, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford 4-acetylamido-3-methyl-5-nitro-phthalicacid dimethyl ester (2.0 g, 71%) as a yellow solid.

Alternative work up for large scale reaction: Reaction mixture waspoured into ice-water, the precipitated solid was isolated byfiltration, washed with water, aq, NaHCO₃ solution, water and dried invacuo to afford the desired product as a light yellow solid.

¹H NMR (CDCl₃, 300 MHz): δ 2.12, 2.40 (2s, 6H); 3.89, 3.90 (2s, 6H);8.25 (s, 1H); 10.27 (s, 1H). ESI-MS (m/z): 311 (M+H⁺).

Synthesis of 4-Amino-3-methyl-5-nitro-phthalic acid dimethyl ester

A solution of 4-acetamido-3-methyl-5-nitro-phthalic acid dimethyl ester(2.8 g, 9.03 mmol) in conc. H₂SO₄ was stirred at room temperature for 2h. The reaction mixture was poured into ice-water (200 mL) and extractedwith EtOAc (2×100 mL). The combined organic layer was washed with water(200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toafford the product 8 (1.8 g, 74%) as a yellow solid.

Synthesis of 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester

To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid dimethyl ester(1.8 g, 6.72 mmol) in THF (10 mL) and water (20 mL) was added 5 N NaOH(4.0 mL) and the resulting mixture was stirred at room temperature for24 h. The reaction mixture was acidified with conc. HCl (pH=2.0) andextracted with EtOAc (2×100 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to afford the4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester (1.3 g, 76%) as ayellow solid.

Synthesis of5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione

To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester(1.3 g, 5.12 mmol), EDCI.HCl (1.07 g, 5.63 mmol) and HOBt (0.69 g, 5.12mmol) was added Et₃N (3.64 mL, 25.6 mL) and stirred at room temperaturefor 10 min. 4-Amino-1-methylpiperidine dihydrochloride (1.04 g, 5.63mmol) was added and the resulting mixture was stirred at roomtemperature for 24 h. The reaction mixture was evaporated in vacuo, theresidue was dissolved in CHCl₃ (200 mL), washed with water (2×100 mL).The organic layer was filtered over Na₂SO₄ and concentrated in vacuo toafford5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione(1.7 g, quant), which was used as such for further reaction.

Synthesis of5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione

To a suspension of5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione(1.7 g, 5.34 mmol) and 10% Pd/C (250 mg) was added MeOH (100 mL)carefully and evacuated in vacuo. The flask was filled with hydrogenunder balloon pressure and stirred for 1 h. The reaction mixture wasfiltered and evaporated in vacuo to afford the crude5,6-diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione(1.5 g, quant.), which was used as such for further reaction.

Synthesis of2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

To a solution of5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione(1.7 g, 5.90 mmol) in MeOH (50 mL) were added AcOH (3 mL) and4-iodo-2-methoxynicotinaldehyde (1.55 g, 5.90 mmol) and the resultingmixture was heated at 60° C. for overnight. The reaction mixture wasevaporated in vacuo and the residue was purified by flash chromatography(5-10% (6% NH₃ in MeOH)/CHCl₃) to afford2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(1.48 g, 47%) as a yellow solid.

Synthesis of2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dioneHydrochloride

To a solution of2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(1.48 g, 2.78 mmol) in 1,4-dioxane (30 mL) was added conc. HCl (3 mL)and the resulting solution was stirred at room temperature forovernight. The solid precipitated was isolated by filtration, washedwith THF (10 mL) and dried in vacuo to afford2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dioneHydrochloride and2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dioneHydrochloride (1.5 g, quant.) as a yellow solid.

Synthesis of2-{[4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hyrdoxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

To a suspension of2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dioneHydrochloride and2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dioneHydrochloride (0.75 g, 1.45 mmol),(R)-3-amino-1-(2,4-dimethylphenoxy)-2-propanol (0.34 g, 1.73 mmol) inEtOH (20 mL) was added Et₃N (0.61 mL, 4.35 mmol) and the resultingmixture was heated at reflux for overnight. The reaction mixture wasevaporated in vacuo and the residue was purified by flash chromatography(10% (6% NH₃/MeOH)/CHCl₃) to afford2-{[4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(0.45 g, 57%) as a yellow solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.58 (d, J=10.8 Hz, 2H); 1.93 (t, J=11.5Hz, 2H); 2.15, 2.19 (2s, 9H); 2.32-2.40 (m, 2H); 2.77-2.88 (m, 6H);3.34-3.70 (m, 2H); 3.91-4.23 (m, 5H), 5.55 (d, J=4.7 Hz, 1H), 6.20 (d,J=7.5 Hz, 1H), 6.78-6.97 (m, 3H), 7.38 (d, J=6.7 Hz, 1H); 7.94 (s, 1H),11.13 (s, 1H), 11.29 (br. s, 1H); 13.32 (s, 1H). ESI-MS m/z 585.5 (MH⁺).Elemental analysis calcd. for C₃₂H₃₆N₆O₅.H₂O: C, 63.77; H, 6.36; N,13.94. Found: C, 63.68; H, 6.24; N, 14.07.

Synthesis of2-{4-[(R)-3-(3-Chloro-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Compound was prepared following the general procedure as describedabove.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.59 (d, J=12.0 Hz, 2H); 1.91-1-99 (m, 3H);2.20 (s, 3H); 2.25 (s, 3H); 2.33-2.44 (m, 2H); 2.75 (s, 3H); 2.82-2.89(m, 3H); 3.34 (br. s, 2H); 3.55-3.74 (m, 2H); 3.90-4.20 (m, 4H); 5.62(d, J=6.0 Hz, 1H); 6.21 (d, J=6.0 Hz, 1H); 6.94-7.17 (m, 4H); 7.40 (br.s, 1H); 7.95 (s, 1H); 11.13 (br. s, 1H); 11.29 (br. s, 1H), 13.42 (s,1H). ESI-MS (m/z): 605.3 and 607.5.

Synthesis of2-{4-[(R)-3-(3-Chloro-2,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Compound was prepared following the general procedure as describedabove.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.59 (d, J=12.0 Hz, 2H); 1.91-1-99 (m, 3H);2.20 (s, 3H); 2.34-2.46 (m, 2H); 2.81 (s, 3H); 2.87-2.90 (m, 3H); 3.34(br. s, 2H); 3.55-3.72 (m, 2H); 3.91-4.10 (m, 4H); 4.28 (d, J=3.0 Hz,2H); 5.62 (d, J=6.0 Hz, 1H); 6.21 (d, J=6.0 Hz, 1H); 7.18-7.41 (m, 4H);7.95 (s, 1H); 11.09 (br. s, 1H); 11.31 (br. s, 1H), 13.42 (s, 1H).ESI-MS (m/z): 627.5.

Synthesis of2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-((S)-1-methyl-piperidin-3-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Compound was prepared following the general procedure as describedabove.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.53-1.61 (m, 1H); 1.72-1.90 (m, 3H);1.99-2.21 (m, 8H); 2.74 (br. s, 2H); 3.35 (s, 3H); 3.47-3.59 (m, 2H);3.94-4.16 (m, 4H); 5.56 (d, J=6.0 Hz, 1H); 6.23 (d, J=6.0 Hz, 1H);6.82-6.97 (m, 3H); 7.40-7.42 (m, 1H); 7.66 (s, 1H), 8.10 (s, 1H); 10.98(br. s, 1H), 11.32 (br. s, 1H); 13.42 (s, 1H). ESI-MS (m/z): 571.3.

Synthesis of2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-((R)-1-methyl-piperidin-3-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Compound was prepared following the general procedure as describedabove.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.53-1.61 (m, 1H); 1.72-1.90 (m, 3H);1.99-2.21 (m, 8H); 2.74 (br. s, 2H); 3.35 (s, 3H); 3.47-3.59 (m, 2H);3.94-4.16 (m, 4H); 5.56 (d, J=6.0 Hz, 1H); 6.23 (d, J=6.0 Hz, 1H);6.82-6.97 (m, 3H); 7.40-7.42 (m, 1H); 7.66 (s, 1H), 8.10 (s, 1H); 10.98(br. s, 1H), 11.32 (br. s, 1H); 13.42 (s, 1H). ESI-MS (m/z): 571.3.

Synthesis of2-{[4-[(R)-3-(5-Chloro-2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Compound was prepared following the general procedure as describedabove.

¹H NMR (DMSO-d₆, 300 MHz): δ 1.62 (d, J=12.0 Hz, 2H); 1.95 (t, J=12.0Hz, 2H); 1.21, 1.23 (2s, 6H); 2.33-2.44 (m, 2H); 2.87 (d, J=9.0 Hz, 2H);3.56-3.74 (m, 2H); 3.88-4.17 (m, 4H); 5.62 (d, J=3.0 Hz, 1H); 6.23 (d,J=6.0 Hz, 1H); 6.84 (d, J=12.0 Hz, 2H); 7.40 (d, J=9.0 Hz, 1H); 7.69 (s,1H); 8.08 (s, 1H); 8.33 (s, 1H); 10.96 (br. s, 1H); 11.32 (br. s, 1H);13.40 (s, 1H). ESI-MS (m/z): 605.3.

Preparation of 1-Amino-3-heteroaryl-2-propanols

General Procedure for the Preparation of(R)-1-Amino-3-indol-1-yl-propan-2-ols: A mixture of(R)—N-(2,3-epoxypropyl)-phthalimide (1.02 g, 5.0 mmol), substitutedindole (5.0 mmol), p-xylene (5 mL) and NaH (80 mg of 60% in mineral oil)was stirred under N₂ at 120° C. for 8 h. After cooling to 80° C. EtOH(10 mL) and anhydrous hydrazine (1 mL) were added, the mixture washeated at 80° C. for 2 h. Then the reaction mixture was cooled to RT,diluted with EtOAc (100 mL), washed with 0.5N NaOH (2×50 mL), brine (50mL). Organic phase was dried over Na₂SO₄, evaporated. The residue wastriturated with Et₂O, the precipitate was collected by filtration, driedin vacuum.

1-((R)-3-Amino-2-hydroxy-propyl)-1H-indole-4-carbonitrile

Tan solid, 0.56 g. LCMS [M+H]⁺ 216.3.

¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, J=8.3 Hz, 1H), 7.47 (d, J=7.5 Hz,1H), 7.34 (d, J=3.6 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.73 (d, J=3.6 Hz,1H), 4.22 (m, 2H), 3.90 (m, 1H), 2.89 (m, 1H), 2.55 (m, 1H).

(R)-1-Amino-3-(5-methoxy-indol-1-yl)-propan-2-ol

Tan solid, 0.27 g. LCMS [M+H]⁺ 221.1.

¹H NMR (300 MHz, CDCl₃): δ 7.25 (d, J=8.5 Hz, 1H), 7.12-7.08 (m, 2H),6.85 (dd, J=2.5, 8.8 Hz, 1H), 6.43 (d, J=3.4 Hz, 1H), 4.12 (m, 2H),3.94-3.80 (m, 4H), 2.82 (dd, J=3.9, 13.1 Hz, 1H), 2.55 (dd, J=7.7, 12.7Hz, 1H).

Synthesis of(R)-2-(4-3-substituted-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

General Procedure

A mixture ofchloropyridone[2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-substituted-imidazo[4,5-f]isoindole-5,7(1H,6H)-dione]or2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-substituted-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one(0.25 mmol), aminoalcohol (0.35 mmol), ethanol (5 mL) and triethylamine(0.35 ml) was stirred at 100° C. overnight. Then reaction was cooled toRT, the solvent was removed in vacuum, the residue was purified by HPLCon a C18 column (acetonitrile-0.1% aq. TFA from 5:95% to 95:5%).

2-{4-[(R)-3-(3-Chloro-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-2,3-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 591.3.

¹H NMR (300 MHz, DMSO): δ 13.45 (br. s., 1H), 11.33 (d, J=6.2 Hz, 1H),10.96 (t, J=5.2 Hz, 1H), 9.85 (br. s., 1H), 7.60-8.20 (br. s., 2H), 7.41(t, J=7.1 Hz, 1H), 7.17 (t, J=8.1 Hz, 1H), 7.04-6.98 (2d, 2H), 6.24 (d,J=8.1 Hz, 1H), 4.40-4.20 (m, 1H), 4.20-4.10 (m, 1H), 4.10-4.00 (m, 2H),3.80-3.70 (m, 1H), 3.60-3.45 (m, 3H), 3.25-3.05 (m, 3H), 2.76 (d, J=4.17Hz, 3H), 2.70-2.50 (m, 2H), 2.30-2.20 (s and m, 4H), 2.00-2.85 (m, 2H).

2-{4-[(R)-3-(3-Chloro-2,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 613.3.

¹H NMR (300 MHz, DMSO): δ 11.35 (d, J=6.2 Hz, 1H), 10.94 (t, J=4.4 Hz,1H), 9.88 (br. s., 1H), 7.99 (br. s., 2H), 7.50-7.15 (m, 3H), 6.22 (d,J=7.1 Hz, 1H), 4.40-4.05 (m, 5H), 3.75-3.60 (m, 1H), 3.60-3.40 (m, 3H),3.25-3.07 (m, 2H), 2.76 (d, J=4.29 Hz, 3H), 2.70-2.50 (m, 2H), 1.94 (m,2H).

2-{4-[(R)-3-(3-Chloro-2-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-2,3-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 595.3.

¹H NMR (300 MHz, DMSO): δ 13.46 (s, 1H), 11.33 (d, J=6.0 Hz, 1H), 10.96(m, 1H), 9.37 (br. s., 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.40 (m, 1H),7.30-7.10 (m, 4H), 6.22 (d, J=7.0 Hz, 1H), 5.73 (br. s., 1H), 4.40-4.10(m, 5H), 3.80-3.60 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.78(d, J=4.20 Hz, 3H), 2.70-2.50 (m, 2H), 2.00 (m, 2H).

2-{4-[(R)-2-Hydroxy-3-(3-trifluoromethylsulfanyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 643.3.

¹H NMR (300 MHz, DMSO): δ 13.45 (br. s. 1H), 11.33 (d, J=6.3 Hz, 1H),10.99 (m, 1H), 9.75 (br. s., 1H), 8.20-7.60 (2H), 7.50-7.20 (m, 5H),6.25 (d, J=7.1 Hz, 1H), 4.40-4.25 (m, 1H), 4.20-4.00 (m, 3H), 3.80-3.65(m, 1H), 3.60-3.45 (m, 4H), 3.23-3.10 (m, 2H), 2.80-2.70 (d, J=4.2 Hz,3H), 2.70-2.50 (m, 2H), 2.00-2.85 (m, 2H).

2-{4-[(R)-2-Hydroxy-3-(2,4,6-trimethyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 585.3.

¹H NMR (300 MHz, DMSO): δ 13.50 (br. s., 0.5H), 11.34 (d, J=6.2 Hz, 1H),10.98 (m, 1H), 9.91 (br. s., 1H), 7.95 (br. s., 2H), 7.42 (t, J=6.9 Hz,1H), 6.81 (s, 2H), 6.25 (d, J=7.9 Hz, 1H), 4.40-425 (m, 1H), 4.20-4.10(m, 1H), 3.85-3.65 (m, 4H), 3.60-3.45 (m, 3H), 3.20-3.05 (m, 2H),2.80-2.70 (m, 3H), 2.70-2.50 (m, 2H), 2.20, 2.17 (two s, 9H), 2.00-1.85(m, 2H).

2-{4-[(R)-3-(3-Chloro-4-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 591.2.

¹H NMR (300 MHz, DMSO): δ 13.50 (br. s., 0.5H), 11.33 (d, J=6.1 Hz, 1H),10.94 (m, 1H), 9.90 (br. s., 1H), 8.10-7.80 (2H), 7.42 (t, J=6.9 Hz,1H), 7.25 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.4,2.4 Hz, 1H), 6.23 (d, J=7.5 Hz, 1H), 4.40-4.25 (m, 1H), 4.15-4.00 (m,3H), 3.75-3.60 (m, 1H), 3.55-3.43 (m, 3H), 3.22-3.08 (m, 2H), 2.80-2.70m, 3H), 2.70-2.50 (m, 2H), 2.25 (s, 3H), 2.00-1.85 (m, 2H).

2-{4-[(R)-3-(2,4-Dimethyl-phenylsulfanyl)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 587.2.

¹H NMR (300 MHz, DMSO): δ 13.43 (br. s., 1H), 11.32 (d, J=6.2 Hz, 1H),10.92 (m, 1H), 9.43 (br. s., 1H), 8.13 (br. s., 1H), 7.87 (br. s., 1H),7.39 (t, J=6.5 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.02 (s, 1H), 6.93 (d,J=7.7 Hz, 1H), 6.14 (d, J=7.5 Hz, 1H), 5.6 (br. s., 1H), 4.32 (m, 1H),3.90 (m, 1H), 3.30-2.90 (m, 5H), 2.80 (s, 3H), 2.70-2.50 (m, 2H),2.30-2.20 (8H), 2.00-1.90 (m, 2H).

2-{4-[(R)-3-(2-tert-Butyl-4-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(free base). LCMS [M+H]⁺ 613.2.

¹H NMR (300 MHz, DMSO): δ 13.41 (br. s., 1H), 11.32 (d, J=6.1 Hz, 1H),11.01 (m, 1H), 8.09 (s, 1H), 7.59 (s., 1H), 7.41 (t, J=6.8 Hz, 1H), 7.06(s, 1H), 6.95-6.85 (m, 2H), 6.21 (d, J=7.5 Hz, 1H), 5.56 (d, J=4.6 Hz,1H), 4.20 (m, 1H), 4.10-3.90 (3H), 3.80-3.70 (m, 1H), 3.65-3.50 (m, 1H),2.95-2.85 (m, 2H), 2.50-2.30 (m, 2H), 2.30-2.20 (7H), 2.10-1.90 m, 2H),1.70-1.60 (m, 2H), 1.38 (s, 9H).

2-{4-[(R)-2-Hydroxy-3-(2,2,3-trifluoro-2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 655.3.

¹H NMR (300 MHz, DMSO): δ 13.44 (br. s., 1H), 11.34 (d, J=5.4 Hz, 1H),10.99 (m, 1H), 9.49 (br. s, 1H), 8.12 (br. s., 1H), 7.84 (m, 1H), 7.40(t, J=6.1 Hz, 1H), 7.20-7.00n (m, 3H), 6.95-6.85 (m, 2H), 6.23 (d, J=7.9Hz, 1H), 5.69 (br. s., 1H), 4.32 (m, 1H), 4.10-3.90 (3H), 3.60-3.40(2H), 3.30-3.05 (m, 2H), 2.79 (s, 3H), 2.70-2.50 (m, 2H), 2.00-1.85 (m,2H).

2-{4-[(R)-2-Hydroxy-3-(2,3,3-trifluoro-2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 655.7.

¹H NMR (300 MHz, DMSO): δ 13.44 (br. s., 1H), 11.33 (d, J=5.4 Hz, 1H),10.99 (m, 1H), 9.44 (br. s, 1H), 8.13 (br. s., 1H), 7.80 (m, 1H), 7.38(t, J=6.1 Hz, 1H), 7.20-6.95 (m, 3H), 6.95-6.80 (m, 2H), 6.23 (d, J=7.9Hz, 1H), 5.72 (br. s., 1H), 4.32 (m, 1H), 4.25-4.15 (3H), 3.30-3.05 (m,2H), 2.79 (m, 3H), 2.70-2.50 (m, 2H), 1.99-1.85 (m, 2H).

2-{4-[(R)-2-Hydroxy-3-(2-methanesulfonylmethyl-4,6-dimethyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 663.7.

¹H NMR (300 MHz, DMSO): δ 13.47 (br. s., 1H), 11.34 (d, J=5.8 Hz, 1H),10.95 (m, 1H), 9.54 (br. s, 1H), 8.13 (br. s., 1H), 7.85 (m, 1H), 7.42(t, J=6.8 Hz, 1H), 7.05-7.00 (m, 2H), 6.24 (d, J=8.0 Hz, 1H), 4.55-4.45(m, 2H), 4.35-4.27 (m, 1H), 4.20-4.10 (m, 1H), 3.95-03.85 (m, 3H),3.25-3.10 (m, 2H), 2.90 (s, 3H), 2.80-2.75 (m, 3H), 2.70-2.50 (m, 2H),2.30-2.20 (8H), 1.99-1.85 (m, 2H).

2-{4-[(R)-3-(3-Chloro-2,6-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 605.3.

¹H NMR (300 MHz, DMSO): δ 13.45 (br. s., 0.5H), 11.34 (d, J=5.7 Hz, 1H),10.98 (m, 1H), 9.86 (br. s, 1H), 7.99 (br. s., 1H), 7.43 (t, J=6.7 Hz,1H), 7.14-7.05 (m, 2H), 6.24 (d, J=7.7 Hz, 1H), 4.35-4.27 (m, 1H),4.20-4.10 (m, 1H), 3.90-3.80 (m, 3H), 3.22-3.10 (m, 2H), 2.90 (m, 3H),2.70-2.50 (m, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 2.00-1.85 (m, 2H).

1-((R)-2-Hydroxy-3-{3-[6-(1-methyl-piperidin-4-yl)-5,7-dioxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-2-oxo-1,2-dihydro-pyridin-4-ylamino}-propyl)-1H-indole-4-carbonitrile.LCMS [M+H]⁺ 591.3.

¹H NMR (300 MHz, DMSO): δ 11.34 (d, J=6.1 Hz, 1H), 10.97 (m, 1H), 9.91(br. s, 1H), 8.03 (br. s., 2H), 7.99 (d, J=8.3 Hz, 1H), 7.72 (d, J=3.6Hz, 1H), 7.55 (d, J=6.7 Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.29-7.22 (m,1H), 6.62 (d, J=3.1 Hz, 1H), 6.16 (d, J=7.2 Hz, 1H), 4.50 (dd, J=13.9,4.1 Hz, 2H), 4.40-4.20 (m, 2H), 3.80-3.60 (m, 2H), 3.57 (s, 1H),3.55-3.42 (m, 3H), 3.22-3.05 (m, 2H), 2.85 (m, 3H), 2.70-2.50 (m, 2H),2.00-1.85 (m, 2H).

2-{4-[(R)-2-Hydroxy-3-(5-methoxy-indol-1-yl)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 596.3.

2-{4-[(R)-3-(3-Chloro-2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-8-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 619.5.

¹H NMR (300 MHz, DMSO): δ 13.35 (s, 1H), 11.30 (d, J=6.6 Hz, 1H), 11.11(m, 1H), 9.39 (br. s, 1H), 7.96 (s, 1H), 7.40 (t, J=6.6 Hz, 1H), 7.08(d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.22 (d, J=8.8 Hz, 1H), 5.59(br. s., 1H), 4.35-4.25 (m, 1H), 4.23-4.15 (m, 1H), 4.12-4.00 (m, 2H),3.80-3.70 (m, 1H), 3.30-3.05 (m, 2H), 2.90-2.70 (7H), 2.24 (s, 7H),2.00-1.85 (m, 2H).

2-{4-[(R)-3-(3-Chloro-4-methoxy-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-8-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione.LCMS [M+H]⁺ 635.5.

¹H NMR (300 MHz, DMSO): δ 13.35 (s, 1H), 11.30 (d, J=5.6 Hz, 1H), 11.11(m, 1H), 9.38 (br. s, 1H), 7.96 (s, 1H), 7.40 (t, J=6.4 Hz, 1H), 6.90(m, 2H), 6.22 (d, J=8.2 Hz, 1H), 5.58 (br. s., 1H), 4.37-4.23 (m, 1H),4.22-4.13 (m, 1H), 4.12-4.00 (m, 3H), 3.85-3.65 (m, 7H), 3.65-3.50 (m,2H), 3.25-3.08 (m, 2H), 2.90-2.70 (m, 7H), 2.35-2.20 (m, 8H), 2.15-2.05(m, 3H), 2.00-1.85 (m, 2H).

Synthesis of Lactam Derivatives

General Procedure.

A mixture of phthalimide-type compound[2-(4-(substituted-amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(R1-substituted)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione](20 mg), AcOH (1.0 mL), Zn (dust) (100 mg) was stirred at 70° C. for 10h. Then the reaction mixture was cooled to RT, filtered, evaporated. Theresidue was purified by preparative HPLC on C18 column(acetonitrile-0.1% TFA) (5:95% to 95:5%).

2-{4-[(R)-2-Hydroxy-3-(3-methoxy-2-methyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 573.3.

2-{4-[(R)-2-Hydroxy-3-(5-methoxy-indol-1-yl)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 583.0.

2-{4-[(R)-2-Hydroxy-1-(1H-imidazol-4-ylmethyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 503.5.

2-{4-[(R)-3-(2,3-Difluoro-4-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 579.5.

2-{4-[(R)-2-Hydroxy-3-(2-trifluoromethoxy-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 613.3.

2-{4-[(R)-2-Hydroxy-3-(2-methylsulfanyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 575.5.

2-[4-((R)-2-Hydroxy-3-o-tolyloxy-propylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 543.5.

2-{4-[(R)-3-(2-Ethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 557.5

2-{4-[(R)-3-(3-Fluoro-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 561.3.

2-{4-[(R)-2-Hydroxy-3-(3-methoxy-2,4-dimethyl-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 587.3.

2-{4-[(R)-3-(3-Chloro-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-oneLCMS [M+H]⁺ 577.5.

¹H NMR (300 MHz, DMSO): δ 13.08 (br. s., 1H), 11.24 (d, J=5.9 Hz, 1H),11.14 (m, 1H), 9.43 (br. s, 1H), 8.02-7.70 (m, 2H), 7.37 (t, J=6.4 Hz,1H), 7.29-6.94 (m, 3H), 6.22 (d, J=7.5 Hz, 1H), 5.58 (br. s., 1H), 4.46(s, 2H), 4.37-4.24 (m, 1H), 4.20-4.11 (m, 1H), 4.08 (s, 2H), 3.77-3.62(m, 1H), 3.25-3.16 (m, 2H), 2.81 (d, J=4.3 Hz, 3H), 2.28 (s, 3H),2.28-2.24 (m, 1H), 2.08 (s, 2H), 2.03-1.96 (m, 3H).

2-{4-[(R)-3-(3-Chloro-2,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one.LCMS [M+H]⁺ 599.5.

¹H NMR (300 MHz, DMSO): δ 13.08 (br. s., 1H), 11.26 (d, J=6.7 Hz, 1H),11.11 (m, 1H), 9.47 (br. s, 1H), 8.05-7.60 (m, 2H), 7.40-6.95 (m, 3H),6.20 (d, J=7.3 Hz, 1H), 5.56 (br. s., 1H), 4.48 (s, 2H), 4.42-4.28 (m,1H), 4.18-4.05 (m, 2H), 3.77-3.62 (m, 1H), 3.60-3.35 (m, 4H), 3.30-3.10(m, 2H), 2.81 (d, J=3.7 Hz, 3H), 2.08 (s, 1H), 2.03-1.90 (m, 3H).

Synthesis of 5,6-diamino-2-(1-methylpiperidin-4-yl)isoindolin-1-one

5,6-Diamino-2-(1-methylpiperidin-4-yl)isoindoline-1-one. A mixture of5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (10.0 g,32.9 mmol), tin powder (39.7 g, 329 mmol), EtOH (300 mL) and conc. HCl(100 mL) was stirred at 75° C. for 4 h. After cooling to RT excess ofTin was removed by filtration, the filtrate was evaporated. The residuewas dissolved in CH₂Cl₂-MeOH (1:1) mixture, basified with NH₄OH.Precipitate formed was removed by filtration, SiO₂ was added to thefiltrate, stirred for 1 h, the solvent was evaporated, the residue wasloaded onto SiO₂ (500 g) column. Eluted with CH₂Cl₂-MeOH—NH₄OH (gradientfrom 100:0:0 to 100:10:1 v/v). Yield 7.86 g (30.2 mmol, 92%) as beigesolid. LCMS [M+H]⁺ 261.4.

¹H NMR (300 MHz, DMSO): δ 6.77 (s, 1H), 6.59 (s, 1H), 5.07 (s, 2H), 4.62(s, 2H), 3.86 (m, 1H), 3.16 (d, J=5.5 Hz, 2H), 2.82 (m, 2H), 2.17 (s,3H), 1.94 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H).

Preparation of 3-chloro-2,4-dimethyl-phenol

Nitration of 2-chloro-m-xylene. Nitric acid (90%, 50 mL) was cooled to−35° C. (ethanol-dry ice bath). 2-Chloro-m-xylene (10 mL) was addeddropwise over 1 h keeping the temperature between −30° C. and −35° C.The reaction mixture was poured onto ice, stirred for 10 min,precipitate formed was collected by filtration, washed with water,dried. The crude product was purified on SiO₂ (50 g), hexane-EtOAc (0 to2% v/v). The product—yellow solid, 12.8 g, as a mixture of2-chloro-1,3-dimethyl-4-nitro-benzene andchloro-1,3-dimethyl-5-nitro-benzene (4:1).

¹H NMR (300 MHz, CDCl₃): δ 7.95 (s, 0.5H) (II), 7.63 (d, J=8.3 Hz, 1.0H)(I), 7.21 (d, J=8.3 Hz, 1H) (I), 2.55 (s, 3H) (I), 2.47 (s, 1.5H) (II),2.45 (s, 3H) (I).

3-Chloro-2,4-dimethyl-aniline. To a solution of a mixture2-chloro-1,3-dimethyl-4-nitro-benzene andchloro-1,3-dimethyl-5-nitro-benzene (12.8 g, 69 mmol) in EtOH (75 mL),conc. HCl (75 mL) was added. Than SnCl₂ (51.0 g) was added in twoportions. The mixture was stirred overnight at RT, then heated at 60° C.for 30 min, cooled to 0-5° C. (ice bath). Neutralized with NaOH (70 g)in H₂O (500 ml). The product was extracted with Et₂O (500 ml). Extractwas dried over Na₂SO₄, evaporated. The residue was crystallized twotimes from hexane providing 3.66 g 3-chloro-2,4-dimethyl-phenylamine aswhite crystals. The filtrates were evaporated in vacuo and the residuewas separated on SiO₂ column (200 g), hexane-EtOAc (0 to 10% v/v).providing additionally 3.11 g of the product. Yield 6.77 g (43.5 mmol,63%).

¹H NMR (300 MHz, CDCl₃): δ 6.89 (d, J=8.3 Hz, 1H), 6.52 (d, J=8.0 Hz,1H), 3.57 (br. s., 2H), 2.27 (s, 3H), 2.24 (s, 3H).

3-Chloro-2,4-dimethylphenol. To a suspension of3-chloro-2,4-dimethyl-aniline (0.47 g, 3.0 mmol), in a mixture of water(3 mL) and conc. H₂SO₄ (2 ml), a solution of Na₂NO₂ (0.22 g) in H₂O (5ml) was added dropwise at 0° C. The mixture was stirred 1 h at 0° C.,than treated with urea (0.2 g), stirred for 10 min at 0° C. A solutionof CuSO₄ (1.0 g) in water (6 mL) was added and the mixture was stirredfor 60 h at RT. The reaction mixture was extracted with CH₂Cl₂ (2×20ml), extracts were dried over Na₂SO₄ and evaporated. The residue wasseparated on SiO₂ (4.0 g) column, hexane-EtOAc (0 to 10%). Browncrystals, 45 mg (0.29 mmol, 10%).

¹H NMR (300 MHz, CDCl₃): δ 6.92 (d, J=8.3 Hz, 1H), 6.59 (d, J=8.1 Hz,1H), 4.96 (br. s., 1H), 2.29 (s, 6H).

Preparation of 3-methoxy-2,4-dimethyl-phenol

2,4-Dihydroxy-3-methyl-benzaldehyde. Phosphorus oxychloride (8.0 mL, 86mmol) was added dropwise with stirring to DMF (26 mL, 0.336 mol) thetemperature being kept at 10-20° C. This reagent was slowly added to asolution of 2-methylresorcinol (4.84 g, 39 mmol) in 26 mL DMF at 20-30°C. After 30 min the reaction mixture was poured in 2 M aq. NaOH (200ml), extracted with Et₂O (2×100 mL), aqueous phase was neutralized with5N aq. HCl, the product was extracted with Et₂O (2×200 mL), dried andevaporated. The residue was separated on SiO₂ (100 g) column,hexane-EtOAc (0 to 20% v/v). Yield 4.1 g (27 mmol, 69%) as white solid.¹H NMR (300 MHz, DMSO): δ 11.61 (s, 1H), 10.79 (s, 1H), 9.71 (s, 1H),7.43 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 1.97 (s, 3H).

4-Benzyloxy-2-hydroxy-3-methyl-benzaldehyde. A mixture of2,4-dihydroxy-3-methyl-benzaldehyde (3.31 g, 21.8 mmol), benzylbromide(4.09 g, 23.9 mmol), NaHCO₃ (5.49 g, 65.4 mmol), 1,4-dioxane (30 mL) andwater (12 mL) was stirred at 60° C. for overnight. Then the reactionmixture was cooled to RT, water (100 mL) was added, extracted with EtOAc(2×200 mL). The extract was dried over Na₂SO₄, evaporated. The residuewas purified on SiO₂ (25 g) column, hexane-EtOAc (0 to 5%). Yield 1.57 g(6.48 mmol, 29%) as off-white solid.

¹H NMR (300 MHz, DMSO): δ 11.38 (s, 1H), 9.82 (s, 1H), 7.62 (d, J=8.7Hz, 1H), 7-84-7.32 (m, 5H), 6.85 (d, J=8.6 Hz, 1H), 5.27 (s, 2H), 2.05(s, 3H).

4-Benzyloxy-2-methoxy-3-methyl-benzaldehyde. A mixture of4-benzyloxy-2-hydroxy-3-methyl-benzaldehyde (1.57 g, 6.49 mmol),dimethylsulfate (1.04 ml, 10.9 mmol), NaOH (1.02 g, 25.5 mmol),1,4-dioxane (20 mL) and water (10 mL) was stirred at 90° C. for 6 h. Thereaction mixture was cooled to RT, water (100 mL) was added, extractedwith EtOAc (150 mL). The extract was washed with brine (100 mL), driedover Na₂SO₄ and evaporated. The residue was purified on SiO₂ (25 g)column, hexane to toluene. Yield 1.20 g (4.68 mmol, 72%), white solid.¹H NMR (300 MHz, DMSO): δ 10.11 (s, 1H), 7.64 (d, J=8.9 Hz, 1H),7.49-7.32 (m, 5H), 7.05 (d, J=8.9 Hz, 1H), 5.24 (s, 2H), 3.81 (s, 3H),2.14 (s, 3H).

3-Methoxy-2,4-dimethyl-phenol. A mixture of4-benzyloxy-2-methoxy-3-methyl-benzaldehyde (1.1 g, 4.68 mmol), 10% Pd/C(0.150 g), MeOH (20 mL) and conc. HCl was stirred under H₂ at RT for 1h. Pd/C was removed by filtration, the filtrate was evaporated, theresidue was purified on SiO₂ column (12 g), hexane —CH₂Cl₂ (100:0 to50:50). Yield 0.67 g (4.40 mmol, 94%), brown oil. ¹H NMR (300 MHz,CDCl₃): δ 6.88 (d, J=8.1 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 4.73 (s, 1H),3.70 (s, 3H), 2.21 (s, 2H), 2.18 (s, 3H).

3-Methoxy-2-methyl-phenol was prepared according to published procedure:J. Org. Chem. 55, 5, 1990, 1469. To a solution of 2.0 g (50 mmol) NaOHand 2-methylresorcinol (6.2 g, 50 mmol) in water (50 mL),dimethylsulfate (4.8 mL, 50 mmol) was added at 95° C. over 30 min, thenreaction was stirred for 2 h at 95° C. After cooling to RT, the reactionmixture was poured into aqueous NaOH (8.0 g in 200 ml H₂O). Extractedwith Et₂O (2×100 mL). The aqueous phase was acidified with 5 N aq. HCl,extracted with Et₂O (2×100 mL), extracts were dried over Na₂SO₄ andevaporated. The residue was purified on SiO₂ (200 g) column,hexane—EtOAc (0 to 20%). Yield 3.37 g (24.0 mmol, 49%), colorless oil.

¹H NMR (300 MHz, DMSO): δ 9.21 (s, 1H), 6.93 (t, J=8.4 Hz, 1H),6.48-6.38 (m, 2H), 3.72 (s, 3H), 1.98 (s, 3H).

Synthesis of Lactams with 2-hydroxyamine Side Chains

Synthesis of the Compounds Illustrated in Scheme 48

4-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione(2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g,12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed ina ChemGlass heavy wall pressure flask. After it was heated at 140° C.for 72 h, the reaction mixture was evaporated to dryness at 95° C. (thebath temperature) under reduced pressure. The chromatography of theresidue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (320:10:1) afforded the titlecompound (2.09 g, 54%). ¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.73 (m, 2H),2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34(s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a mixture of4-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (5.0 g, 12.8 mmol) and 10% Pd/C (500 mg) was added2-propanol (20 mL), and then MeOH (230 mL). After it was stirred underatmospheric hydrogen pressure for 4 h, the reaction mixture was filteredthrough Celite. The filtrate was mixed with 4-iodo-2-methoxynicotinicaldehyde (3.37 g, 12.8 mmol) and AcOH (13 mL), stirred at the roomtemperature for 16 h, and evaporated under reduced pressure to afford acrude, which was mixed with HCl in 1,4-dioxane (4 M, 60 mL) and H₂O (5mL), heated at 70° C. for 1.5 h and evaporated at 95° C. (the bathtemperature) to dryness. Et₃N (5.35 mL, 38.4 mmol) was added to thesolution of the residue in CH₂Cl₂ (250 mL) at 0° C. under N₂, followedby the addition of the solution of Boc₂O (3.35 g, 15.4 mmol). After itwas stirred at 0° C. for 1 h and at the room temperature for 19 h, thereaction mixture was mixed slowly with MeOH (200 mL) at 0° C. and thenevaporated at 70° C. (the bath temperature) to dryness under reducedpressure. The residue was mixed with(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (2.5 g, 12.8 mmol) andEt₃N (5.35 mL, 38.4 mmol) in EtOH (200 mL) resulting a mixture, whichwas heated at 100° C. for 5 h and then concentrated. Chromatography ofthe residual mixture with CH₂Cl₂/MeOH/28% aqueous NH₄OH (250:10:1)furnished a fluorescent product which was mixed with zinc dust (5.5 g,84 mmol) and AcOH (200 mL). After it was heated at 90° C. for 2 h, thereaction mixture was filtered and the filtrate was concentrated at 70°C. (the bath temperature) under reduced pressure. The residue was mixedwith HCl in dioxane (4 M, 60 mL) and H₂O (5 mL), heated at 70° C. for2.5 h and evaporated at 95° C. (the bath temperature) to dryness. Theresidue was basified with NH₃ in EtOH (2 M) and concentrated.Chromatography of the crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (40:10:1)afforded a fluorescent product (6.5 g). 50 mg of this product wassubjected to HPLC purification to furnish the title compound in TFA saltform (37 mg). ¹H NMR (DMSO-d₆) δ 1.90-2.05 (4H), 2.19 (s, 3H, CH₃), 2.22(s, 3H, CH₃), 3.13 (m, 2H), 3.42 (m, 2H), 3.55 (m, 1H), 3.69 (m, 1H),4.03 (m, 2H), 4.13 (m, 1H), 4.39 (m, 1H), 4.46 (s, 2H), 6.22 (d, J=7 Hz,1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.39 (d,J=7 Hz, 1H), 7.55 (br s, 1H), 7.85 (br s, 1H), 11.14 (br s, 1H, NH),11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 543.5 (MH⁺).

3-[4-(2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-oxo-5,7-dihydro-1H-1,3,6-triaza-s-indacen-6-yl)-piperidin-1-yl]-propionitrile:To a solution of the TFA salt of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(40 mg, 0.061 mmol) in MeOH (2.4 mL) was added DIEA (600 μL, 3.4 mmol)at 0° C. under N₂ resulting a mixture which was stirred under N₂ at 0°C. for 20 min and followed by addition of acrylonitrile (197 μL, 3.0mmol) via a syringe. The reaction mixture was stirred under N₂ at 0° C.for 1 h and at the room temperature for 1 h and then evaporated. Theresidue was subjected to HPLC purification to afford the title compoundin TFA salt form. ¹H NMR (DMSO-d₆) δ 1.99-2.13 (4H), 2.19 (s, 3H, CH₃),2.22 (s, 3H, CH₃), 3.12 (m, 2H), 3.22 (m, 2H), 3.47 (m, 2H), 3.51-3.75(4H), 4.01 (m, 2H), 4.13 (m, 1H), 4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d,J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.96 (s, 1H),7.36 (d, J=7 Hz, 1H), 7.59 (br s, 1H), 7.86 (br s, 1H), 11.13 (br s, 1H,NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 596.5 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:A mixture of the TFA salt of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(40 mg, 0.061 mmol) and methyl vinyl sulfone (318.4 mg, 3.0 mmol) inEtOH (2.0 mL) was heated at 90° C. for 22 h and then evaporated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(125:10:1) afforded a fluorescent product which was subjected to HPLCpurification to afford the title compound in TFA salt form. ¹H NMR(DMSO-d₆) δ 2.01-2.17 (4H), 2.19 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 3.15(s, 3H, CH₃), 3.23 (m, 2H), 3.51-3.75 (8H), 4.01 (m, 2H), 4.15 (m, 1H),4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H),6.94 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.36 (dd, J=7 Hz and 6 Hz, 1H), 7.59(br s, 1H), 7.83 (br s, 1H), 11.14 (br s, 1H, NH), 11.23 (br d, J=6 Hz,1H, NH); ESI-MS m/z 649.5 (MH⁺).

6-(1-Cyclopropylmethyl-piperidin-4-yl)-2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a solution of the TFA salt of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(40 mg, 0.061 mmol) and cyclopropanecarbaldehyde (150 μL, 2.0 mmol) in amixed solvent of CH₃CN (6 mL) and H₂O (2 mL) was added AcOH (500 μL) at0° C. and the resulting reaction mixture was stirred at 0° C. for 20 minand followed by addition of Na(OAc)₃BH (254 mg, 1.2 mmol). The reactionmixture was stirred at 0° C. for 1 h and at the room temperature for 1 hand then evaporated. The residue was subjected to HPLC purification toafford the title compound in TFA salt form. ¹H NMR (DMSO-d₆) δ 0.39 (m,2H), 0.67 (m, 2H), 1.10 (m, 1H), 2.03 (m, 2H), 2.12 (m, 2H), 2.19 (s,3H, CH₃), 2.21 (s, 3H, CH₃), 3.01 (m, 2H), 3.18 (m, 2H), 3.50-4.15 (7H),4.32 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H),6.91 (d, J=7 Hz, 1H), 6.97 (s, 1H), 7.38 (d, J=7 Hz, 1H), 7.57 (br s,1H), 7.82 (br s, 1H), 11.13 (br s, 1H, NH), 11.22 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 597.3 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-ethyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:¹H NMR (DMSO-d₆) δ 1.00 (t, J=6 Hz, 3H), 1.70 (m, 2H), 1.80 (m, 2H),2.02 (m, 2H), 2.18 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.33 (m, 2H), 2.98(m, 2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.97-4.08 (3H), 4.12 (m, 1H), 4.42(s, 1HO, 4.46 (s, 1H), 5.47 (d, J=4 Hz, 0.5H, NH), 5.53 (d, J=4 Hz,0.5H, NH), 6.20 (d, J=7 Hz, 0.5H), 6.21 (d, J=7 Hz, 0.5H), 6.81 (d, J=7Hz, 1H), 6.90 (s, 1H), 6.95 (d, J=7 Hz, 1H), 7.37 (s, 0.5H), 7.31 (d,J=7 Hz, 1H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (brd, J=7 Hz, 1H, NH), 11.19 (br s, J=7 Hz, 1H, NH); ESI-MS m/z 571.3(MH⁺).

Synthesis of the Compounds Illustrated by Scheme 49

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(3.0 g, 5.26 mmol) was mixed with zinc dust (6.88 g, 10.52 mmol) in AcOH(150 mL). After it was heated at 90° C. for 2 h, the reaction mixturewas filtered and the filtrate was evaporated at 95° C. (the bathtemperature) under reduced pressure to dryness. The residue was basifiedwith 28% aqueous NH₄OH solution and concentrated. Chromatography of theresidual crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (90:10:1) afforded thetitle compound (2.45 g, 84%). ¹H NMR (DMSO-d₆) δ 1.70 (m, 2H), 1.80 (m,2H), 2.05 (m, 2H), 2.20 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.28 (s, 3H,CH₃), 2.89 (m, 2H), 3.57 (m, 1H), 3.79 (m, 1H), 3.95-4.09 (3H), 4.11 (m,1H), 4.40 (s, 1H), 4.45 (s, 1H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.54 (d,J=3 Hz, 0.5H, NH), 6.21 (m, 1H), 6.80-7.00 (3H), 7.30-7.39 (1.5H), 7.69(s, 0.5H), 7.79 (s, 0.5H), 7.93 (s, 0.5H), 11.12 (br d, J=6 Hz, 1H, NH),11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 557.7 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-8-methyl-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:¹H NMR (DMSO-d₆) δ 1.70 (m, 2H), 1.82 (m, 2H), 2.01 (m, 2H), 2.16 (s,3H, CH₃), 2.18 (s, 3H, CH₃), 2.20 (s, 3H, CH₃), 2.50 (s, 2H, CH₃ on thebenzoimidazole), 2.89 (m, 2H), 3.53 (m, 1H), 3.69 (m, 1H), 3.98-4.11(3H), 4.18 (m, 1H), 4.41 (s, 2H), 5.53 (br s, 1H, NH), 6.19 (d, J=7 Hz,1H), 6.79 (d, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 6.95 (s, 1H), 7.35 (d,J=7 Hz, 1H), 7.79 (s, 1H), 11.35 (br s, 1H, NH); ¹H NMR (MeOH-d₄) δ 1.78(m, 2H), 1.87 (m, 2H), 2.12 (s, 3H, CH₃), 2.13 (m, 2H), 2.14 (s, 3H,CH₃), 2.25 (s, 3H, CH₃), 2.42 (s, 2H, CH₃ on the benzoimidazole), 2.89(m, 2H), 3.58 (m, 1H), 3.72 (m, 1H), 4.01 (m, 2H), 4.11 (m, 1H), 4.20(m, 2H), 4.18 (m, 1H), 4.38 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.69 (d, J=7Hz, 1H), 6.79 (d, J=7 Hz, 1H), 6.85 (s, 1H), 7.20 (d, J=7 Hz, 1H), 7.65(s, 1H); ESI-MS m/z 571.7 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:¹H NMR (DMSO-d₆) δ 1.67 (m, 2H), 1.82 (m, 2H), 2.00 (m, 2H), 2.16 (s,3H, CH₃), 2.20 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.80 (s, 2H, CH₃ on thebenzoimidazole), 2.85 (m, 2H), 3.56 (m, 1H), 3.68 (m, 1H), 3.96-4.11(3H), 4.17 (m, 1H), 4.39 (br s, 2H), 5.50 (br s, 1H, NH), 6.19 (d, J=7Hz, 1H), 6.79 (d, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 6.95 (s, 1H), 7.35(d, J=7 Hz, 1H), 7.60 (s, 1H), 11.20 (br s, 1H, NH); 11.30 (br s, 1H,NH); ESI-MS m/z 571.7 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(36.1 mg, 0.066 mmol) was mixed with zinc dust (100 mg) in AcOH (4 mL)and the reaction mixture was heated at 90° C. for 2 h. After it wascooled to the room temperature, the upper clear layer of the reactionmixture was evaporated and the residue was subjected to HPLCpurification to afford the title compound in TFA salt form (9.2 mg,22%). ¹H NMR (DMSO-d₆) δ 1.90-2.15 (4H), 2.75 (s, 3H, CH₃), 3.21 (m,2H), 3.42-3.60 (2H), 3.65 (m, 1H), 4.31 (m, 1H), 4.50 (s, 2H), 4.98 (m,1H), 6.19 (d, J=6 Hz, 1H), 7.31-7.41 (3H), 7.51 (d, J=6 Hz, 1H), 7.63(s, 1H), 7.78 (s, 1H), 7.90 (s, 1H), 9.60 (br s, 1H), 11.06 (br s, 1H,NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 533.5 (MH⁺).

Lactams with Sulfonamide Side Chains

N-(2-Amino-ethyl)-2-bromo-benzenesulfonamide: To solution of(2-amino-ethyl)-carbamic acid tert-butyl ester (208 mg, 1.3 mmol) inCH₂Cl₂ (20 mL) was added DIEA (300 μL, 1.72 mmol) at 0° C., followed bythe addition of 2-bromo-benzenesulfonyl chloride (383 mg, 1.5 mmol).After it was stirred at 0° C. for 1 h and at the room temperature foranother 16 h, the reaction mixture was evaporated thoroughly. Theresidue was diluted with 20% TFA in CH₂Cl₂ (10 mL), stirred for 3 h atthe room temperature, and evaporated. Chromatography of the residualcrude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (90:10:1) afforded the titlecompound (313 mg, 86%). ¹H NMR (DMSO-d₆) δ 2.86 (t, J=8 Hz, 2H), 3.04(t, J=8 Hz, 2H), 7.55-7.65 (2H), 7.89 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz,1H); ESI-MS m/z 279.1 (MH⁺).

2-Bromo-N-(2-{3-[6-(1-methyl-piperidin-4-yl)-7-oxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-2-oxo-1,2-dihydro-pyridin-4-ylamino}-ethyl)-benzenesulfonamide:To a solution of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(40 mg, 0.1 mmol) and N-(2-amino-ethyl)-2-bromo-benzenesulfonamide (56mg, 0.20 mmol) in EtOH (4 mL) was added Et₃N (500 μL, 3.6 mmol) and thereaction was heated at 95° C. for 16 h. The solvent was evaporated invacuo and the residue was purified by flash chromatography withCH₂Cl₂/MeOH/28% aqueous NH₄OH (100:10:1) afforded the title compound(7.3 mg, 11%). ¹H NMR (DMSO-d₆) δ 1.70 (m, 2H), 1.85 (m, 2H), 2.15 (m,2H), 2.29 (s, 3H, CH₃), 2.96 (m, 2H), 3.19 (m, 1H), 3.50 (m, 2H), 4.05(m, 1H), 4.48 (s, 1H), 6.05 (d, J=7 Hz, 1H), 7.32 (br s, 1H), 7.38-7.50(1.5H), 7.62-7.70 (1.5H), 7.82 (s, 0.5H), 7.87 (s, 0.5H), 7.96-7.99(2H), 8.20) br S, 1H, NH), 11.02 (br s, 1H, NH), 11.26 (br s, 1H, NH);ESI-MS m/z 640.5 (MH⁺).

Synthesis of Phenol and Pyrimidinone Derivatives

Synthesis of the Compounds Illustrated in Scheme 51

3-Bromo-2-(5,5-dimethyl-[1,3]dioxan-2-yl)-6-methoxy-phenol: A mixture of6-bromo-2-hydroxy-3-methoxy-benzaldehyde (2.31 g, 10.0 mmol), neopentylglycol (1.14 g, 11.0 mmol), TsOH (9.5 mg) and triethyl orthoformate(1.93 g, 13.0 mmol) were heated at 110° C. for 30 min and thenpartitioned between NaHCO₃ (300 mL) solution and EtOAc (200 mL). Theaqueous layer was extracted with EtOAc (3×30 mL) and the combinedextracts were washed with brine and dried through Na₂SO₄. Evaporation ofsolvent afforded the title compound (3.17 g, 100%). ¹H NMR (CDCl₃) δ0.85 (s, 3H), 1.27 (s, 3H), 3.70 (s, 2H), 3.82 (s, 2H), 3.85 (s, 3H),5.90 (s, 1H), 6.72 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H).

2-(6-Bromo-3-methoxy-2-methoxymethoxy-phenyl)-5,5-dimethyl-[1,3]dioxane:To the solution of3-bromo-2-(5,5-dimethyl-[1,3]dioxan-2-yl)-6-methoxy-phenol in DCM (20mL) was added DIEA (697 μL, 4 mmol), followed by addition ofchloromethoxymethane (228 μL, 3 mmol). After it was stirred at the roomtemperature for 72 h, the reaction mixture was evaporated and theresidue was partitioned between NaHCO₃ (50 mL) solution and EtOAc (40mL). The aqueous layer was extracted with EtOAc (3×10 mL) and thecombined extracts were washed with brine and dried through Na₂SO₄.Evaporation of solvent afforded the title compound. ¹H NMR (CDCl₃) δ0.80 (s, 3H), 1.45 (s, 3H), 3.57 (s, 3H), 3.65 (d, J=12 Hz, 2H), 3.79(s, 3H), 3.80 (d, J=12 Hz, 2H), 5.11 (s, 2H), 6.00 (s, 1H), 6.76 (d, J=8Hz, 1H), 7.32 (d, J=8 Hz, 1H).

(R)-1-[2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-4-methoxy-3-methoxymethoxy-phenylamino]-3-(2,4-dimethyl-phenoxy)-propan-2-ol:A mixture of2-(6-bromo-3-methoxy-2-methoxymethoxy-phenyl)-5,5-dimethyl-[1,3]dioxane(36 mg, 0.1 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (30mg, 0.15 mmol), CuI (51.4 mg, 0.27 mmol), ethylene glycol (168 mg, 2.7mmol), and K₃PO₄ (573 mg, 2.7 mmol) in 2-propanol (8 mL) was heated at90° C. in a sealed vial for 14 h and evaporated. Chromatography of theresidue with hexanes and EtOAc afforded the title compound (305 mg,71%). ¹H NMR (CDCl₃) δ 0.79 (s, 3H, CH₃), 1.29 (s, 3H, CH₃), 2.21 (s,3H, CH₃), 2.25 (s, 3H, CH₃), 2.95 (br s, 1H, OH), 3.30 (m, 1H), 3.49 (s,3H, OCH₃), 3.51 (m, 1H), 3.65 (m, 2H), 3.75 (s, 3H, OCH₃), 3.77 (m, 2H),4.00 (m, 2H), 4.25 (m, 1H), 5.09 (s, 2H), 6.05 (s, 1H), 6.48 (d, J=8 Hz,1H), 6.69 (d, J=8 Hz, H), 6.82 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H),6.95 (s, 1H). ESI-MS m/z 476.8 (MH⁺).

2-{6-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-hydroxy-3-methoxy-phenyl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a solution of(R)-1-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4-methoxy-3-methoxymethoxy-phenylamino]-3-(2,4-dimethyl-phenoxy)-propan-2-ol(102 mg, 0.21 mmol) in THF (5.0 mL) was added 36% aqueous HCl (1.0 mL).After it was heated at 50° C. for 1.5 h, the reaction mixture wasevaporated and the residue was mixed with5,6-diamino-2-(1-methyl-piperidin-4-yl)-2,3-dihydro-isoindol-1-one (76mg, 0.21 mmol) and AcOH (0.4 mL) in EtOH (8 mL). The mixture was stirredat the room temperature for 30 min, heated at 80° C. for 1.5 h, andevaporated to dryness. Chromatography of the residual crude withCH₂Cl₂/MeOH/28% aqueous NH₄OH (40:10:1) afforded the title compound (13mg, 10%). ESI-MS m/z 586.5 (MH⁺).

Synthesis of Pyrimidinone Derivatives

Synthesis of the Compounds Illustrated by Scheme 51

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (177 mg, 1.0mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (195.3 mg,1.0 mmol) in chloroform (8 mL) was added Et₃N (348 μL, 2.5 mmol). Afterit was stirred at the room temperature for 8 h, the reaction mixture wasevaporated under reduced pressure thoroughly. The remaining residue wasmixed with 5,6-diamino-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione(274 mg, 1.0 mmol) in DMA (10 mL). After it was heated at 110° C. for 14h, the reaction mixture was cooled to the room temperature and mixedwith aqueous HCl solution (12 N, 1 mL). The resulting mixture was heatedin a sealed vial at 110° C. for 3 h and evaporated to dryness. Theresidue was basified with NH₃ in EtOH (2 M) and concentrated.Chromatography of the crude afforded the title compound (93 mg, 17%yield for 3 steps). ¹H NMR (DMSO-d₆) δ 1.62 (m, 2H), 1.97 (m, 2H), 2.14(s, 3H, CH₃), 2.17 (s, 3H, CH₃), 2.17 (s, 3H, CH₃), 2.38 (m, 2H), 2.89(m, 2H), 3.80 (m, 1H), 3.90-4.02 (4H), 4.11 (m, 1H), 5.47 (br s, 1H,NH), 6.82 (d, J=6 Hz, 1H), 6.93 (d, J=6 Hz, 1H), 6.97 (s, 1H), 8.06 (s,1H), 8.12 (s, 1H), 10.83 (br s, 1H, NH); ESI-MS m/z 572.3 (MH⁺).

2-{6-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-4-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(60.1 mg, 0.105 mmol) was mixed with zinc dust (300 mg) in AcOH (12 mL)resulting a mixture which was heated at 90° C. for 1 h, then cooled tothe room temperature and filtered. The filtrate was evaporated, theresidue was basified with NH₃ in EtOH (2 M) and purified bychromatography with CH₂Cl₂/MeOH/28% aqueous NH₄OH (60:10:1) to furnish afluorescent product which was subjected to HPLC purification to affordthe title compound in TFA salt form (42 mg, 60%). ¹H NMR (DMSO-d₆) δ1.90-2.15 (4H), 2.13 (s, 3H, CH₃), 2.20 (s, 3H, CH₃), 2.81 (s, 3H, CH₃),3.20 (m, 2H), 3.40-3.60 (4H), 3.97 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H),4.40 (s, 2H), 4.46 (s, 2H), 6.83 (d, J=6 Hz, 1H), 6.93 (d, J=6 Hz, 1H),6.96 (s, 1H), 7.53 (br s, 1H), 7.75 (s, 1H), 9.75 (br s, 1H); ESI-MS m/z560.5 (MH⁺).

Synthesis of Additional Phthalimide Derivatives

Synthesis of the Compound Illustrated by Scheme 53

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-1H-1,3,6-triaza-s-indacene-5,7-dione:To a mixture of4-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (203 mg, 0.52 mmol) and 10% Pd/C (20 mg) was added2-propanol (2 mL), and then MeOH (50 mL). After it was stirred underatmospheric hydrogen pressure for 3 h, the reaction mixture was filteredthrough Celite. The filtrate was mixed with 4-iodo-2-methoxynicotinicaldehyde (137 mg, 0.52 mmol) and AcOH (3 mL), stirred at the roomtemperature for 14 h, and evaporated under reduced pressure to afford acrude, which was mixed with HCl in dioxane (4 M, 15 mL) and H₂O (1 mL),heated at 70° C. for 4 h and evaporated at 95° C. (the bath temperature)to dryness. The residue was mixed with(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (117 mg, 0.6 mmol) andEt₃N (418 μL, 3 mmol) in EtOH (8 mL) resulting a mixture, which washeated at 95° C. for 18 h and then concentrated. Chromatography of theresidual mixture with CH₂Cl₂/MeOH/28% aqueous NH₄OH (100:10:1) furnisheda fluorescent product that was subjected to HPLC purification to furnishthe title compound in TFA salt form (6.23 mg, 1.9%). ¹H NMR (DMSO-d₆) δ1.90 (m, 2H), 2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 3.10 (m, 2H),3.30-3.42 (4H), 3.49 (m, 1H), 3.72 (m, 1H), 4.01 (m, 2H), 4.15 (m, 1H),4.39 (m, 1H), 5.58 (br s, 1H, NH), 6.24 (d, J=7 Hz, 1H), 6.84 (d, J=7Hz, 1H), 6.93 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.40 (d, J=7 Hz, 1H), 7.66(br s, 1H), 8.11 (br s, 1H), 10.96 (br s, 1H, NH), 11.31 (br d, J=6 Hz,1H, NH); ESI-MS m/z 557.7 (MH⁺).

Synthesis of the Compounds Illustrated by Scheme 54

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a mixture of4-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (203 mg, 0.52 mmol) and 10% Pd/C (20 mg) was added2-propanol (2 mL), and then MeOH (50 mL). After it was stirred underatmospheric hydrogen pressure for 3 h, the reaction mixture was filteredthrough Celite. The filtrate was mixed with 4-iodo-2-methoxynicotinicaldehyde (137 mg, 0.52 mmol) and AcOH (3 mL), stirred at the roomtemperature for 14 h, and evaporated under reduced pressure to afford acrude, which was mixed with HCl in dioxane (4 M, 15 mL) and H₂O (1 mL),heated at 70° C. for 4 h and evaporated at 95° C. (the bath temperature)to dryness. To the residue and acetaldehyde (150 μL, 2.6 mmol) in amixture of CH₃CN (6 mL) and H₂O (2 mL) at 0° C., was added AcOH (500 μL)and the resulting mixture was stirred at 0° C. for 20 min, followed byaddition of Na(OAc)₃BH (762 mg, 3.6 mmol). The reaction mixture wasstirred at 0° C. for 1 h and at the room temperature for 1 h and thenevaporated. The chromatography of the residue with CH₂Cl₂/MeOH/28%aqueous NH₄OH (70:10:1) afforded the title compound (143 mg, 67%).ESI-MS m/z 426.0 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(143 mg, 0.336 mmol) and(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (78 mg, 0.403 mmol) inEtOH (200 mL) was added Et₃N (5.35 mL, 38.4 mmol) and the mixture washeated at 95° C. for 16.5 h and then concentrated. Chromatography of thecrude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (160:10:1) (65 mg, 33%). ¹H NMR(DMSO-d₆) δ 1.02 (t, J=6 Hz, 3H), 1.63 (m, 2H), 1.83 (m, 2H), 2.19 (s,3H, CH₃), 2.21 (s, 3H, CH₃), 2.29-2.40 (4H), 2.98 (m, 2H), 3.53 (m, 1H),3.70 (m, 1H), 3.91-4.08 (3H), 4.18 (m, 1H), 5.52 (d, J=4 Hz, 1H, NH),6.23 (d, J=7 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 6.91 (d, J=7 Hz, 1H), 6.97(s, 1H), 7.38 (d, J=7 Hz, 1H), 7.65 (s, 1H), 8.09 (br s, 1H), 10.95 (brs, 1H, NH), 11.08 (br s, 1H, NH); ESI-MS m/z 585.5 (MH⁺).

Synthesis of the Compound Illustrated by Scheme 55

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(1-imino-ethyl)-piperidin-4-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione:A mixture of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-1H-1,3,6-triaza-s-indacene-5,7-dione(109 mg, 0.2 mmol) and ethyl acetimidate (3 g) in Et₃N (8 mL) wasstirred at the room temperature for 110 h. After it was concentrated at35° C. (the bath temperature) under reduced pressure, the mixture wassubjected to chromatography [CH₂Cl₂/MeOH/28% aqueous NH₄OH (90:10:1)] tofurnish a fluorescent product which was purified again with HPLC toafford the title compound in TFA salt form (5.06 mg, 3.6%). ¹H NMR(DMSO-d₆) δ 1.93 (m, 2H), 2.19 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.35 (s,3H, CH₃), 3.26 (m, 1H), 3.40 (m, 1H), 3.58 (m, 1H), 3.86 (m, 1H),3.91-4.26 (7H), 4.43 (m, 1H), 6.23 (d, J=7 Hz, 1H), 6.86 (d, J=7 Hz,1H), 6.92 (d, J=7 Hz, 1H), 7.00 (s, 1H), 7.41 (d, J=7 Hz, 1H), 7.71 (s,1H), 8.10 (s, 1H), 8.68 (br s, 1H, NH), 9.21 (br s, 1H, NH), 10.97 (brs, 1H, NH), 11.30 (br s, 1H, NH); ESI-MS m/z 598.7 (MH⁺).

Synthesis of Additional Phthalimide Derivatives

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of5-amino-2-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-6-nitro-isoindole-1,3-dione(90.0 mg, 0.258 mmol) in MeOH (30 mL) was added 10 mg of Pd/C (10%) andAcOH (1.5 mL) (the solution was purged with N₂ before adding Pd/C).After it was stirred under H₂ for 2 h, the reaction mixture was filteredthrough Celite. To the filtrate was added 4-iodo-2-methoxynicotinicaldehyde (100.0 mg, 0.38 mmol) and the resulting mixture was stirred atthe room temperature for 1 h and heated at 80° C. for 3 h, and thenevaporated to dryness under reduced pressure. The residue was mixed with4 M HCl/dioxane (8 mL) and H₂O (0.6 mL), heated at 70° C. for 1 h andevaporated to dryness under reduced pressure. The chromatography of thecrude residue (50:10:1 CH₂Cl₂/MeOH/28% aqueous NH₄OH) afforded thecorresponding chloropyridone intermediate (73 mg, 62% for 3 steps),which was then mixed with (S)-2-amino-1-(3-chloro-phenyl)-ethanol (12mg, 0.06 mmol) and Et₃N (18 mg, 0.18 mmol) in EtOH (1.5 mL). After itwas heated at 95° C. for 23 h, the reaction mixture was concentrated andsubjected to HPLC purification to furnish the title compound (40.3 mg,34% for the last step). ¹H NMR (DMSO-d₆) δ 1.50 (m, 2H), 1.83 (2H), 1.98(m, 1H), 2.19 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.90 (m, 2H), 3.11 (m,2H), 3.21-3.62 (6H), 3.70 (m, 2H), 4.00 (m, 2H), 4.15 (m, 1H), 5.32 (brs, 1H, OH), 5.55 (br s, 1H, NH), 6.24 (d, J=6 Hz, 1H), 6.80-7.00 (3H),7.40 (m, 1H), 7.59 (s, 1H), 8.13 (s, 1H), 9.10 (br s, 1H), 10.96 (br s,1H, NH), 11.32 (br s, 1H, NH); ESI-MS m/z 615.5 (MH⁺).

2-{4-[(R)-3-(3-Chloro-2-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.50 (m, 2H), 1.83 (2H), 1.98 (m, 1H), 2.28 (s, 3H,CH₃), 2.90 (m, 2H), 3.11 (m, 2H), 3.21-3.62 (6H), 3.70 (m, 2H), 4.10 (m,2H), 4.19 (m, 1H), 5.32 (br s, 1H, OH), 5.55 (br s, 1H, NH), 6.24 (d,J=6 Hz, 1H), 6.99-7.07 (2H), 7.15 (m, 1H), 7.40 (m, 1H), 7.71 (s, 1H),8.14 (s, 1H), 9.12 (br s, 1H), 10.97 (br s, 1H, NH), 11.31 (br s, 1H,NH); ESI-MS m/z 635.5 (MH⁺).

2-{4-[(R)-3-(3-Chloro-2,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.50 (m, 2H), 1.83 (2H), 1.95 (m, 1H), 2.28 (s, 3H,CH₃), 2.90 (m, 2H), 3.11 (m, 2H), 3.21-3.59 (6H), 3.70 (m, 2H), 4.10 (m,1H), 4.29 (m, 2H), 5.32 (br s, 1H, OH), 5.56 (br s, 1H, NH), 6.24 (d,J=6 Hz, 1H), 7.20 (m, 1H), 7.33 (m, 1H), 7.41 (m, 1H), 7.85 (s, 1H),8.15 (s, 1H), 9.13 (br s, 1H), 10.94 (br s, 1H, NH), 11.35 (br s, 1H,NH); ESI-MS m/z 657.3 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-pyrrolidin-1-yl-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.78-2.09 (6H), 2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃),3.00 (m, 2H), 3.21 (m, 2H), 3.49-3.79 (6H), 4.00 (m, 2H), 4.18 (m, 1H),5.56 (br s, 1H, NH), 6.21 (d, J=6 Hz, 1H), 6.80-6.98 (3H), 7.40 (m, 1H),7.70 (s, 1H), 8.14 (s, 1H), 9.51 (br s, 1H), 10.95 (br s, 1H, NH), 11.33(br s, 1H, NH); ESI-MS m/z 585.3 (MH⁺).

Synthesis of Additional Phthalimide Derivatives

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.216g, 4.0 mmol) in MeOH (47.5 mL) was added 120 mg of Pd/C (10%) (thesolution was purged with N₂ before adding Pd/C) and AcOH (2.5 mL). Afterit was stirred under atmospheric H₂ for 5 h, the reaction mixture wasfiltered through Celite. To the filtrate was added4-iodo-2-methoxynicotinic aldehyde (1.052 g, 4.0 mmol) and the resultingmixture was stirred at the room temperature for 17 h, heated at 80° C.for 5 h, and then evaporated to dryness under reduced pressure. Theresidue was mixed with 4 M HCl/dioxane (40 mL) and H₂O (3 mL), heated at70° C. for 3 h and was evaporated under reduced pressure. Thechromatography of the crude residue (150:10:1 CH₂Cl₂/MeOH/28% aqueousNH₄OH) afforded the title compound (688 mg, 42% for 3 steps). ¹H NMR(DMSO-d₆) δ 1.65 (m, 2H), 2.05 (m, 2H), 2.24 (s, 3H), 2.40 (m, 2H), 2.92(m, 2H), 4.01 (m, 1H), 6.60 (d, 1H, J=6.9 Hz), 7.70 (d, J=6.9 Hz, 1H),8.03 (s, 1H), 8.05 (s, 1H); ESI-MS m/z 412.4 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(448.3 mg, 1.35 mmol) and(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (303.0 mg, 1.55 mmol)in EtOH (10 mL) was added Et₃N (410 mg, 4.05 mmol). After it was heatedat 100° C. for 14 h, the reaction mixture was concentrated under reducedpressure. The chromatography of the crude residue (150:10:1CH₂Cl₂/MeOH/28% aqueous NH₄OH) afforded the title compound (498 mg,45%). ¹H NMR (DMSO-d₆) δ 1.60 (m, 2H), 1.95 (m, 2H), 2.18 (s, 3H, CH₃),2.18 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.39 (m, 2H), 2.90 (m, 2H), 3.57(m, 1H), 3.71 (m, 1H), 3.90-4.08 (3H), 4.18 (m, 1H), 5.55 (d, J=6 Hz,1H, NH), 6.22 (d, J=6 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 6.92 (d, J=6 Hz,1H), 6.97 (s, 1H), 7.39 (d, J=6 Hz, 1H), 7.64 (s, 1H), 8.09 (s, 1H),10.96 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 571.3 (MH⁺).

2-{4-[(S)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.60 (m, 2H), 1.95 (m, 2H), 2.18 (s, 3H, CH₃), 2.18(s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.39 (m, 2H), 2.90 (m, 2H), 3.57 (m,1H), 3.71 (m, 1H), 3.90-4.08 (3H), 4.18 (m, 1H), 5.55 (d, J=6 Hz, 1H,NH), 6.22 (d, J=6 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 6.92 (d, J=6 Hz, 1H),6.97 (s, 1H), 7.39 (d, J=6 Hz, 1H), 7.64 (s, 1H), 8.09 (s, 1H), 10.96(br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 571.3 (MH⁺).

2-{4-[2-Hydroxy-3-(3-methoxy-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.65 (m, 2H), 2.00 (m, 2H), 2.28 (s, 3H, CH₃), 2.39(m, 2H), 2.95 (m, 2H), 3.57 (m, 1H), 3.71 (m, 1H), 3.73 (s, 3H, CH₃),3.90-4.08 (3H), 4.15 (m, 1H), 5.59 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz,1H), 6.50-6.62 (3H), 7.18 (s, 1H), 7.39 (s, 1H), 7.73 (s, 1H), 8.11 (s,1H), 10.97 (br s, 1H, NH), 11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z573.3 (MH⁺).

2-{4-[3-(4-tert-Butyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.22 (s, 9H), 1.62 (m, 2H), 1.98 (m, 2H), 2.20 (s,3H, CH₃), 2.39 (m, 2H), 2.89 (m, 2H), 3.53 (m, 1H), 3.64 (m, 1H),3.90-4.08 (3H), 4.15 (m, 1H), 5.59 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz,1H), 6.90 (d, J=6 Hz, 2H), 7.27 (d, J=6 Hz, 2H), 7.40 (s, 1H), 7.81 (s,1H), 8.11 (s, 1H), 10.98 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MSm/z 599.5 (MH⁺).

2-{4-[3-(4-Chloro-3-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.62 (m, 2H), 1.95 (m, 2H), 2.20 (s, 3H, CH₃), 2.28(s, 3H, CH₃), 2.40 (m, 2H), 2.87 (m, 2H), 3.50-4.50 (4H), 5.62 (d, J=6Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.00 (s, 1H),7.28 (d, J=6 Hz, 1H), 7.39 (d, J=6 Hz, 1H), 7.76 (s, 1H), 8.10 (s, 1H),10.96 (br s, 1H, NH), 11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 591.3(MH⁺).

2-{4-[2-Hydroxy-3-(2-methoxy-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.53 (m, 2H), 2.69 (s, 3H, CH₃), 3.18(m, 2H), 3.42-3.62 (3H), 3.74 (m, 1H), 3.80 (s, 3H, CH₃), 4.01 (m, 2H),4.15 (m, 1H), 4.30 (m, 1H), 5.59 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H),6.82-7.04 (4H), 7.39 (s, 1H), 7.80 (s, 1H), 8.13 (s, 1H), 9.60 (br s,1H), 10.97 (br s, 1H, NH), 11.33 (br d, J=6 Hz, 1H, NH); ESI-MS m/z573.3 (MH⁺).

2-{4-[2-Hydroxy-3-(4-methoxy-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.53 (m, 2H), 2.80 (s, 3H, CH₃), 3.20(m, 2H), 3.42-3.80 (4H), 3.70 (s, 3H, CH₃), 3.99 (m, 2H), 4.10 (m, 1H),4.30 (m, 1H), 5.59 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.80-6.97 (4H),7.40 (s, 1H), 7.79 (s, 1H), 8.13 (s, 1H), 9.60 (br s, 1H), 10.97 (br s,1H, NH), 11.32 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 573.3 (MH⁺).

2-{4-[3-(3-Chloro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.57 (m, 2H), 2.79 (s, 3H, CH₃), 3.19(m, 2H), 3.35-3.60 (3H), 3.65 (m, 1H), 4.02-4.19 (3H), 4.31 (m, 1H),5.65 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.95-7.05 (3H), 7.30 (m, 1H),7.39 (m, 1H), 7.79 (s, 1H), 8.10 (s, 1H), 9.62 (br s, 1H), 10.95 (br s,1H, NH), 11.32 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 577.3 (MH⁺).

2-{4-[3-(4-Chloro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.57 (m, 2H), 2.79 (s, 3H, CH₃), 3.19(m, 2H), 3.52 (m, 2H), 3.69 (m, 1H), 4.06 (m, 2H), 4.15 (m, 1H), 4.35(m, 1H), 5.65 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H), 7.02 (d, J=6 Hz,2H), 7.30 (d, J=6 Hz, 2H), 7.40 (m, 1H), 7.80 (s, 1H), 8.13 (s, 1H),9.60 (br s, 1H), 10.95 (br s, 1H, NH), 11.32 (br d, J=6 Hz, 1H, NH);ESI-MS m/z 577.3 (MH⁺).

2-[4-(2-Hydroxy-3-phenoxy-propylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.67 (m, 2H), 2.10 (m, 2H), 2.30 (s, 3H, CH₃), 2.42(m, 2H), 2.95 (m, 2H), 3.51 (m, 1H), 3.68 (m, 2H), 3.95-4.06 (3H), 4.15(m, 1H), 5.61 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.95 (m, 1H),6.99 (d, J=6 Hz, 2H), 7.30 (m, 2H), 7.39 (m, 1H), 7.74 (s, 1H), 8.11 (s,1H), 9.60 (br s, 1H), 10.98 (br s, 1H, NH), 11.31 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 543.3 (MH⁺).

2-[4-(2-Hydroxy-2-pyridin-4-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.68 (m, 2H), 2.19 (m, 2H), 2.28 (s, 3H, CH₃), 2.41(m, 2H), 2.98 (m, 2H), 3.49 (m, 1H), 3.71 (m, 2H), 4.02 (m, 1H), 4.99(m, 1H), 6.09 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 7.41 (d, J=6Hz, 1H), 7.54 (d, J=6 Hz, 2H), 7.80 (s, 1H), 8.11 (m, 1H), 8.54 (d, J=6Hz, 2H), 10.88 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 514.5(MH⁺).

2-{4-[(R)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.57 (m, 2H), 2.79 (s, 3H, CH₃), 3.19(m, 2H), 3.52 (m, 2H), 3.69 (m, 1H), 4.06 (m, 2H), 4.12 (m, 1H), 4.33(m, 1H), 5.65 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.99-7.17 (4H), 7.40(m, 1H), 7.77 (s, 1H), 8.13 (s, 1H), 9.69 (br s, 1H), 10.97 (br s, 1H,NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 561.3 (MH⁺).

2-{4-[(S)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.57 (m, 2H), 2.79 (s, 3H, CH₃), 3.19(m, 2H), 3.52 (m, 2H), 3.69 (m, 1H), 4.06 (m, 2H), 4.12 (m, 1H), 4.33(m, 1H), 5.65 (br s, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.99-7.17 (4H), 7.40(m, 1H), 7.77 (s, 1H), 8.13 (s, 1H), 9.69 (br s, 1H), 10.97 (br s, 1H,NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 561.3 (MH⁺).

2-{4-[(S)-1-Hydroxymethyl-2-(1H-imidazol-4-yl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (MeOH-d₄) δ 2.10 (m, 2H), 2.83 (m, 2H), 2.96 (s, 3H, CH₃),3.16-3.36 (4H), 3.67 (m, 2H), 3.85 (m, 2H), 4.33 (m, 1H), 4.47 (m, 1H),6.23 (d, J=7 Hz, 1H), 7.28 (d, J=7 Hz, 1H), 7.53 (s, 1H), 7.86 (s, 1H),7.86 (s, 1H), 8.78 (s, 1H); ESI-MS m/z 517.5 (MH⁺).

2-{4-[(R)-1-Hydroxymethyl-2-(1H-imidazol-4-yl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (MeOH-d₄) δ 2.10 (m, 2H), 2.83 (m, 2H), 2.96 (s, 3H, CH₃),3.16-3.36 (4H), 3.67 (m, 2H), 3.85 (m, 2H), 4.33 (m, 1H), 4.47 (m, 1H),6.23 (d, J=7 Hz, 1H), 7.28 (d, J=7 Hz, 1H), 7.53 (s, 1H), 7.86 (s, 1H),7.86 (s, 1H), 8.78 (s, 1H); ESI-MS m/z 517.5 (MH⁺).

2-[4-((R)-1-Hydroxymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (MeOH-d₄) δ 2.08 (m, 2H), 2.83 (m, 2H), 2.88-3.28 (4H), 2.89 (s,3H, CH₃), 3.68 (m, 2H), 3.79 (m, 2H), 4.03 (m, 1H), 4.43 (m, 1H), 6.08(d, J=6 Hz, 1H), 7.10-7.30 (6H), 7.78 (s, 1H), 7.78 (s, 1H); ESI-MS m/z527.3 (MH⁺).

2-{4-[2-(1H-Imidazol-4-yl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.58 (m, 2H), 2.03 (m, 2H), 2.23 (s, 3H, CH₃), 2.40(m, 2H), 2.87-3.95 (4H), 3.78 (m, 2H), 3.99 (m, 1H), 4.37 (t, J=6 Hz,1H, NH), 6.19 (d, J=6 Hz, 1H), 7.04 (s, 1H), 6.99-7.17 (4H), 7.41 (m,1H), 7.58 (s, 1H), 7.90 (s, 1H), 8.10 (s, 1H), 10.70 (br s, 1H, NH),11.31 (br s, 1H, NH); ESI-MS m/z 487.5 (MH⁺).

2-{4-[(R)-2-Hydroxy-3-(5-methyl-indol-1-yl)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.25-2.77 (2H), 2.37 (s, 3H, CH₃), 2.79(m, 2H), 3.19 (s, 3H, CH₃), 3.30 (m, 1H), 3.52 (m, 2H), 4.12-4.39 (3H),5.70 (br s, 1H, NH), 6.10 (d, J=7 Hz, 1H), 6.39 (s, 1H), 6.95 (d, J=7Hz, 1H), 7.29-7.49 (4H), 7.99 (br s, 1H), 8.15 (br s, 1H), 9.50 (br s,1H), 10.97 (br s, 1H, NH), 11.35 (br s, J=6 Hz, 1H, NH); ESI-MS m/z580.8 (MH⁺).

2-{4-[1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.40 (s, 3H, CH₃), 1.98 (m, 2H), 2.55 (m, 2H), 2.80(s, 3H, CH₃), 3.18 (m, 2H), 3.53 (m, 2H), 4.11 (m, 1H), 4.23-4.45 (3H),4.51 (m, 1H), 6.32 (d, J=7 Hz, 1H), 6.80-6.99 (4H), 7.45 (m, 1H), 7.94(br s, 1H), 8.15 (br s, 1H), 9.57 (br s, 1H), 11.20 (d, J=7 Hz, 1H, NH),11.41 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 555.3 (MH⁺).

2-{4-[2-Hydroxy-3-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.80-1.99 (6H), 2.50-2.65 (4H), 2.80 (s, 3H, CH₃),2.99-3.28 (6H), 3.45-3.72 (4H), 3.97 (m, 2H), 4.11 (m, 1H), 4.31 (m,1H), 6.17-6.29 (2H), 6.65 (d, J=7 Hz, 1H), 7.40 (m, 1H), 7.80 (br s,1H), 8.15 (br s, 1H), 9.57 (br s, 1H), 10.95 (br s, 1H, NH), 11.33 (brd, J=6 Hz, 1H, NH); ESI-MS m/z 638.7 (MH⁺).

2-{4-[(R)-2-Hydroxy-3-(naphthalen-1-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.84 (m, 2H), 2.55 (m, 2H), 2.78 (s, 3H, CH₃), 3.18(m, 2H), 3.55 (m, 2H), 3.70 (m, 1H), 3.80 (m, 1H), 4.22-4.38 (4H), 5.78(s, 1H, NH), 6.31 (d, J=7 Hz, 1H), 7.01 (d, J=7 Hz, 1H), 7.35-7.60 (6H),7.89 (d, J=7 Hz, 1H), 8.11 (s, 1H), 8.33 (d, J=7 Hz, 1H), 11.04 (br s,1H, NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 593.3 (MH⁺).

2-{4-[(R)-2-Hydroxy-3-(naphthalen-2-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.99 (m, 2H), 2.55 (m, 2H), 2.78 (s, 3H, CH₃), 3.18(m, 2H), 3.48-3.65 (3H), 3.75 (m, 1H), 4.18-4.38 (4H), 5.72 (s, 1H, NH),6.29 (d, J=7 Hz, 1H), 7.21-7.48 (5H), 7.75-7.89 (4H), 8.11 (s, 1H), 9.60(br s, 1H), 11.02 (br s, 1H, NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MSm/z 593.3 (MH⁺).

2-{4-[(R)-3-(Biphenyl-3-yloxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.99 (m, 2H), 2.55 (m, 2H), 2.78 (s, 3H, CH₃), 3.18(m, 2H), 3.49-3.65 (4H), 3.71 (m, 1H), 4.19 (m, 2H), 4.31 (m, 1H), 5.68(s, 1H, NH), 6.25 (d, J=7 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 7.20-7.49 (7H),7.59 (d, J=7 Hz, 2H), 7.70 (s, 1H), 8.12 (s, 1H), 9.60 (br s, 1H), 11.01(br s, 1H, NH), 11.33 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 619.3 (MH⁺).

2-(4-{(R)-2-Hydroxy-3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenoxy]-propylamino}-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.99 (m, 2H), 2.55 (m, 2H), 2.79 (s, 3H, CH₃), 3.18(m, 2H), 3.32-3.63 (4H), 3.70 (m, 1H), 4.09-4.20 (3H), 4.32 (m, 1H),5.68 (d, J=3 Hz, 1H, NH), 6.21 (d, J=7 Hz, 1H), 6.85-7.06 (3H),7.35-7.48 (2H), 7.77 (s, 1H), 8.13 (s, 1H), 9.60 (br s, 1H), 10.99 (brs, 1H, NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 659.5 (MH⁺).

4-((R)-2-Hydroxy-3-{3-[6-(1-methyl-piperidin-4-yl)-5,7-dioxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-2-oxo-1,2-dihydro-pyridin-4-ylamino}-propoxy)-3-methoxy-benzonitrile:¹H NMR (DMSO-d₆) δ 2.00 (m, 2H), 2.55 (m, 2H), 2.81 (s, 3H, CH₃), 3.18(m, 2H), 3.40-3.59 (3H), 3.69 (m, 1H), 3.93 (s, 3H, CH₃), 4.09-4.21(3H), 4.32 (m, 1H), 5.70 (br s, 1H, NH), 6.21 (d, J=7 Hz, 1H), 7.19 (d,J=7 Hz, 1H), 7.37-7.47 (3H), 7.79 (s, 1H), 8.13 (s, 1H), 9.59 (br s,1H), 10.98 (br s, 1H, NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z598.5 (MH⁺).

2-{4-[(R)-2-Hydroxy-3-(2,3,4-trimethoxy-phenoxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.99 (m, 2H), 2.58 (m, 2H), 2.81 (s, 3H, CH₃), 3.18(m, 2H), 3.38-3.59 (2H), 3.68-3.85 (2H), 3.75 (s, 3H, CH₃), 3.77 (s, 3H,CH₃), 3.79 (s, 3H, CH₃), 4.02 (m, 2H), 4.15 (m, 1H), 4.32 (m, 1H), 5.70(br s, 1H, NH), 6.23 (d, J=7 Hz, 1H), 6.68 (d, J=7 Hz, 1H), 6.78 (d, J=7Hz, 1H), 7.41 (m, 1H), 7.75 (s, 1H), 8.13 (s, 1H), 9.59 (br s, 1H),10.98 (br s, 1H, NH), 11.34 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 633.5(MH⁺).

2-{4-[(R)-3-(3,5-Dimethyl-pyrazol-1-yl)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.11 (s, 3H, CH₃), 2.23 (s, 3H, CH₃),2.56 (m, 2H), 2.78 (s, 3H, CH₃), 3.18 (m, 2H), 3.35 (m, 1H), 3.56 (m,1H), 4.01-4.18 (3H), 4.32 (m, 1H), 5.80 (s, 1H), 6.12 (d, J=7 Hz, 1H),6.68 (d, J=6 Hz, 1H), 7.40 (m, 1H), 7.99 (br s, 1H), 8.13 (br s, 1H),9.56 (br s, 1H), 10.99 (br s, 1H, NH), 11.34 (br d, J=6 Hz, 1H, NH);ESI-MS m/z 545.3 (MH⁺).

Synthesis of Additional Phthalimide Derivatives

Synthesis of the Compound Illustrated by Scheme 58

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of5-amino-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-nitro-isoindole-1,3-dione(40 mg, 0.12 mmol) in THF (6 mL) was added Raney Ni in H₂O (1 mL) andcyclohexa-1,4-diene (800 μL). After it was stirred at the roomtemperature for 30 min, the reaction mixture was loaded directly on thetop of a column and washed with CH₂Cl₂/MeOH/28% aqueous NH₄OH (90:10:1).The residue obtained from evaporation of the wash was mixed with4-iodo-2-methoxynicotinicaldehyde (34 mg, 0.13 mmol) and AcOH (0.5 mL)in MeOH (10 mL). The mixture was stirred at the room temperature for 64h, concentrated under reduced pressure, mixed with 4 M HCl/dioxane (8mL) and H₂O (0.6 mL), heated at 50° C. for 1.5 h, and concentrated underreduced pressure to give a crude, which was subjected to HPLCpurification to furnish a fluorescent product in TFA salt form.(R)-1-Amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (45 mg, 0.24 mmol) andEt₃N (70 μL, 0.5 mmol) were added into the solution of this fluorescentproduct and the mixture was evaporated after 17.5 h of heating at 80° C.The residual crude was subjected to HPLC to afford the title compound inTFA salt form (7.86 mg, 9.2%). ¹H NMR (DMSO-d₆) δ 2.13 (s, 3H, CH₃),2.19 (s, 3H, CH₃), 3.02-4.05 (16H), 4.15 (m, 1H), 5.35 (br s, 1H, OH),5.53 (br s, 1H, OH), 6.23 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.92(d, J=7 Hz, 1H), 6.98 (s, 1H), 7.39 (d, J=7 Hz, 1H), 7.65 (s, 1H), 8.11(s, 1H), 9.78 (br s, 1H, NH), 10.94 (br s, 1H, NH), 11.30 (br s, 1H,NH); ESI-MS m/z 602.5 (MH⁺).

Synthesis of the Compounds Illustrated by Scheme 59

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[(S)-1-(tetrahydro-furan-2-yl)methyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of5-amino-6-nitro-2-[(S)-1-(tetrahydro-furan-2-yl)methyl]-isoindole-1,3-dione(29.1 mg, 0.1 mmol) in MeOH (30 mL) was added 3 mg of Pd/C (10%) (thesolution was purged with N₂ before adding Pd/C). After it was stirredunder atmospheric H₂ for 2 h, the reaction mixture was filtered throughCelite. To the filtrate was added AcOH (1.5 mL) and4-iodo-2-methoxynicotinic aldehyde (26.3 mg, 0.1 mmol) and the resultingmixture was stirred at the room temperature for 18 h and heated at 75°C. for 4 h, and then evaporated to dryness under reduced pressure. Theresidue was mixed with 4 M HCl/dioxane (8 mL) and H₂O (0.6 mL), heatedat 70° C. for 4 h and evaporated to dryness under reduced pressure. Theresidue was subjected to HPLC purification to furnish the correspondingchloropyridone intermediate, which was then mixed with(S)-2-amino-1-(3-chloro-phenyl)-ethanol (7 mg, 0.02 mmol) and Et₃N (10mg, 0.1 mmol) in EtOH (1.5 mL). After it was heated at 100° C. for 17 h,the reaction mixture was concentrated and subjected to HPLC purificationto furnish the title compound (15.8 mg, 30% for 4 steps). ¹H NMR(DMSO-d₆) δ 1.50-1.99 (4H), 3.52-3.79 (6H), 4.13 (m, 1H), 4.99 (m, 1H),6.00 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.30-7.39 (3H), 7.50 (d, J=6Hz, 1H), 7.63 (s, 1H), 7.88 (s, 1H), 8.14 (s, 1H); 10.90 (br s, 1H, NH),11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 534.2 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.40-3.75 (2H), 4.98 (m, 1H), 6.01 (br s, 1H, NH),6.20 (d, J=6 Hz, 1H), 7.35-7.44 (3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s,1H), 7.84 (s, 1H), 8.11 (s, 1H), 10.91 (br s, 1H, NH), 11.07 (br s, 1H,NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 450.4 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.66 (m, 2H), 2.06 (m, 2H), 2.25 (s, 3H, CH₃), 2.39(m, 2H), 2.93 (m, 2H), 3.57 (m, 1H), 3.67 (m, 1H), 3.96 (m, 1H), 4.98(m, 1H), 6.01 (s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.39 (3H), 7.50(d, J=6 Hz, 1H), 7.63 (s, 1H), 7.86 (s, 1H), 8.11 (s, 1H), 10.89 (br s,1H, NH), 11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 547.5 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methoxy-ethyl)-piperidin-4-ylmethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.51 (m, 2H), 1.80-2.01 (3H), 2.92 (m, 2H), 3.25 (m,2H), 3.29 (s, 3H), 3.42-3.78 (8H), 5.00 (m, 1H), 6.01 (br s, 1H, NH),6.20 (d, J=6 Hz, 1H), 7.32-7.39 (3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s,1H), 7.89 (s, 1H), 8.15 (s, 1H), 10.87 (br s, 1H, NH), 11.30 (br d, J=6Hz, 1H, NH); ESI-MS m/z 605.2 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-hydroxy-1-hydroxymethyl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.51-3.85 (6H), 4.27 (m, 1H), 4.89 (br s, 2H, OH),4.99 (m, 1H), 6.01 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.41 (3H),7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.85 (s, 1H), 8.11 (s, 1H), 10.89(br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 524.5 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-hydroxy-2,2-dimethyl-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 0.85 (6H), 3.01 (s, 2H), 3.47 (s, 2H), 3.61 (m, 1H),3.69 (m, 1H), 4.57 (br s, 1H, OH), 4.99 (m, 1H), 6.01 (br s, 1H, NH),6.20 (d, J=6 Hz, 1H), 7.32-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s,1H), 7.88 (s, 1H), 8.16 (s, 1H), 10.89 (br s, 1H, NH), 11.29 (br d, J=6Hz, 1H, NH); ESI-MS m/z 536.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-pyridin-3-yl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.05 (m, 2H), 3.57 (m, 1H), 3.67 (m, 1H), 3.89 (m,2H), 4.98 (m, 1H), 5.95 (br s, 1H, NH), 6.19 (d, J=6 Hz, 1H), 7.30-7.41(3H), 7.45-7.64 (3H), 7.80-8.13 (3H), 8.40-8.55 (2H), 10.89 (br s, 1H,NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 555.7 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-pyridin-4-yl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.16 (m, 2H), 3.60 (m, 1H), 3.70 (m, 1H), 3.97 (m,2H), 4.98 (m, 1H), 5.99 (br s, 1H, NH), 6.19 (d, J=6 Hz, 1H), 7.19-7.79(7H), 7.80-8.19 (2H), 8.61-8.73 (2H), 10.89 (br s, 1H, NH), 11.29 (br d,J=6 Hz, 1H, NH); ESI-MS m/z 555.7 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-((R)-2-methoxy-1-methyl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.23 (s, 3H), 3.50 (m, 1H), 3.60 (m, 1H), 3.69 (m,1H), 3.87 (t, J=9 Hz, 1H), 4.48 (m, 1H), 4.99 (m, 1H), 6.00 (br s, 1H,NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.42 (3H), 7.50 (d, J=6 Hz, 1H), 7.63(s, 1H), 7.86 (s, 1H), 8.11 (s, 1H), 10.88 (br s, 1H, NH), 11.29 (br d,J=6 Hz, 1H, NH); ESI-MS m/z 522.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-((S)-2-hydroxy-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.09 (d, J=6 Hz, 3H, CH₃), 3.43 (m, 1H), 3.56 (m,2H), 3.67 (m, 1H), 3.95 (m, 1H), 4.89 (m, 1H, OH), 4.99 (m, 1H), 6.00(br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.30-7.39 (3H), 7.50 (d, J=6 Hz,1H), 7.63 (s, 1H), 7.90 (s, 1H), 8.13 (s, 1H), 10.90 (br s, 1H, NH),11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 508.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 2.26 (s, 3H, CH₃), 3.18 (m, 2H), 3.50-3.82 (4H), 4.98(m, 1H), 5.97 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.30-7.39 (3H), 7.50(d, J=6 Hz, 1H), 7.63 (s, 1H), 7.87 (s, 1H), 8.11 (s, 1H), 8.80 (s, 1H),10.88 (br s, 1H, NH), 11.28 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 575.3(MH⁺).

2-(4-((S)-2-(3-chlorophenyl)-2-hydroxyethylamino)-2-oxo-1,2-dihydropyridin-3-yl-6-((S)-quinuclidin-3-yl)imidazo[4,5-f]isoindole-5,7-(1H,6H)-dione:¹H NMR (DMSO-d₆) δ 1.72-2.18 (5H), 3.42-4.18 (8H), 4.72 (m, 1H), 4.99(m, 1H), 6.01 (br s, 1H, NH), 6.21 (d, J=6 Hz, 1H), 7.31-7.41 (3H), 7.50(d, J=6 Hz, 1H), 7.64 (s, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 9.86 (br s,1H), 10.87 (br s, 1H, NH), 11.31 (br d, J=6 Hz, 1H, NH); ESI-MS m/z559.3 (MH⁺).

2-(4-((S)-2-(3-chlorophenyl)-2-hydroxyethylamino)-2-oxo-1,2-dihydropyridin-3-yl-6-((R)-quinuclidin-3-yl)imidazo[4,5-f]isoindole-5,7-(1H,6H)-dione:¹H NMR (DMSO-d₆) δ 1.72-2.18 (5H), 3.42-3.79 (7H), 4.13 (m, 1H), 4.72(m, 1H), 4.99 (m, 1H), 6.01 (br s, 1H, NH), 6.21 (d, J=6 Hz, 1H),7.31-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.85 (s, 1H), 8.16(s, 1H), 9.86 (br s, 1H), 10.87 (br s, 1H, NH), 11.31 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 559.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-pyrrolidin-1-yl-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.80-2.11 (6H), 3.02 (m, 2H), 3.23 (m, 2H), 3.40-3.75(6H), 4.99 (m, 1H), 6.00 (br s, 1H, NH), 6.21 (d, J=6 Hz, 1H), 7.31-7.41(3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.90 (s, 1H), 8.15 (s, 1H),9.56 (br s, 1H), 10.88 (br s, 1H, NH), 11.30 (br d, J=6 Hz, 1H, NH);ESI-MS m/z 561.0 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-methoxy-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.27 (s, 3H, CH₃), 3.52-3.79 (6H), 4.99 (m, 1H), 6.00(br s, 1H, NH), 6.19 (d, J=6 Hz, 1H), 7.31-7.41 (3H), 7.50 (d, J=6 Hz,1H), 7.63 (s, 1H), 7.88 (s, 1H), 8.13 (s, 1H), 10.89 (br s, 1H, NH),11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 508.4 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-hydroxy-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.50-3.75 (6H), 4.88 (br s, 1H, OH), 4.99 (br s, 1H),6.00 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.42 (3H), 7.50 (d, J=6Hz, 1H), 7.64 (s, 1H), 7.87 (s, 1H), 8.13 (s, 1H), 10.90 (br s, 1H, NH),11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 494.4 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-hydroxy-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.76 (m, 2H), 3.45-3.72 (6H), 4.52 (br s, 1H, OH),4.98 (br s, 1H), 6.00 (br s, 1H, NH), 6.19 (d, J=6 Hz, 1H), 7.32-7.42(3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.87 (s, 1H), 8.12 (s, 1H),10.90 (br s, 1H, NH), 11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 508.5(MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-imidazol-1-yl-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 2.21 (m, 2H), 3.55-3.79 (4H), 4.28 (m, 2H), 4.99 (brs, 1H), 6.01 (br s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.42 (3H), 7.50(d, J=6 Hz, 1H), 7.63 (s, 1H), 7.68 (s, 1H), 7.83 (s, 1H), 7.89 (s, 1H),8.15 (s, 1H), 9.09 (s, 1H), 10.88 (br s, 1H, NH), 11.31 (br d, J=6 Hz,1H, NH); ESI-MS m/z 558.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2,3-dihydroxy-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.51-3.65 (3H), 3.69 (m, 1H), 3.84 (m, 1H), 4.68 (m,1H), 4.93 (m, 1H), 4.99 (m, 1H), 6.00 (d, J=6 Hz, NH), 6.20 (d, J=6 Hz,1H), 7.32-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.88 (s, 1H),8.13 (s, 1H), 10.91 (br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MSm/z 524.5 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.81 (m, 2H), 1.92 (m, 2H), 2.22 (m, 2H), 3.25 (m,2H), 3.38 (m, 2H), 3.500-3.73 (4H), 4.98 (m, 1H), 6.00 (br s, 1H, NH),6.19 (d, J=6 Hz, 1H), 7.31-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s,1H), 7.87 (s, 1H), 8.13 (s, 1H), 10.89 (br s, 1H, NH), 11.29 (br d, J=6Hz, 1H, NH); ESI-MS m/z 575.5 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[2-(1H-imidazol-4-yl)-ethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 3.02 (m, 2H), 3.58 (m, 1H), 3.69 (m, 1H), 3.88 (m,2H), 4.98 (br s, 1H), 5.76 (s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.32-7.42(3H), 7.49-7.52 (2H), 7.63 (s, 1H), 7.90 (br s, 1H), 8.05 (br s, 1H),9.00 (s, 1H), 10.88 (br s, 1H, NH), 11.31 (br d, J=6 Hz, 1H, NH); ESI-MSm/z 544.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.23 (d, J=9 Hz, 2H), 1.58 (d, J=9 Hz, 2H), 1.70 (m,1H), 1.95 (m, 2H), 2.39 (m, 2H), 2.87 (m, 2H), 3.35 (m, 2H), 3.42-3.52(2H), 3.61 (m, 1H), 3.69 (1H), 4.39 (br s, 1H, OH), 4.99 (m, 1H), 6.00(s, 1H, NH), 6.21 (d, J=6 Hz, 1H), 7.32-7.42 (3H), 7.50 (d, J=6 Hz, 1H),7.63 (s, 1H), 7.87 (s, 1H), 8.13 (s, 1H), 10.89 (br s, 1H, NH), 11.30(br s, 1H, NH); ESI-MS m/z 591.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(3-morpholin-4-yl-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.76 (m, 2H), 2.20-2.38 (6H), 3.32-3.48 (4H),3.52-3.77 (4H), 4.99 (m, 1H), 6.00 (s, 1H, NH), 6.19 (d, J=6 Hz, 1H),7.31-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.87 (s, 1H), 8.13(s, 1H), 9.56 (br s, 1H), 10.89 (br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 577.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(2-pyrrolidin-1-yl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.81 (m, 2H), 2.03 (m, 2H), 3.15 (m, 2H), 3.50 (m,2H), 3.53-3.74 (4H), 3.95 (m, 2H), 4.99 (m, 1H), 6.00 (s, 1H, NH), 6.21(d, J=6 Hz, 1H), 7.29-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.64 (s, 1H),7.92 (s, 1H), 8.18 (s, 1H), 9.61 (br s, 1H), 10.88 (br s, 1H, NH), 11.30(br d, J=6 Hz, 1H, NH); ESI-MS m/z 547.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.43-1.68 (4H), 1.87-2.11 (4H), 2.20 (s, 3H, CH₃),2.93 (m, 1H), 3.52-3.75 (4H), 4.99 (m, 1H), 6.00 (s, 1H, NH), 6.21 (d,J=6 Hz, 1H), 7.29-7.41 (3H), 7.50 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.87(s, 1H), 8.13 (s, 1H), 10.89 (br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 561.3 (MH⁺).

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.90 (m, 2H), 2.50-3.80 (14H), 2.70 (s, 3H, CH₃),4.99 (m, 1H), 6.01 (s, 1H, NH), 6.20 (d, J=6 Hz, 1H), 7.30-7.41 (3H),7.50 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.90 (s, 1H), 8.14 (s, 1H), 10.87(br s, 1H, NH), 11.30 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 590.5 (MH⁺).

Synthesis of2-{4-[(R)-3-(2-bromo-4-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

A mixture of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dionedihydrochloride (4) (85 mg, 18 mmol),(R)-1-amino-3-(2-bromo-5-fluorophenoxy)-propan-2-ol (50 mg, 0.18 mmol)and Et₃N (375 mg, 3.71 mmol) in EtOH (4 mL) was heated at 100° C. for 12h. The filtrate was concentrated and the residue was passed throughsmall silica gel column (10% NH₄OH in MeOH/CH₂Cl₂ (1:9). Columnfractions were concentrated and obtained compound was subjected to HPLCpurification to afford2-{4-[(R)-3-(2-bromo-5-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-oneas TFA salt (5) (30 mg, 21%). ¹H NMR (DMSO-d₆) 01.80-2.15 (m, 4H), 2.80(s, 3H), 3.10-3.3 (m, 2H), 3.40-4.15 (m, 7H), 4.05-4.20 (m, 2H),4.23-4.40 (m, 1H), 4.45 (s, 2H), 5.0 (br, 1H), 6.24 (d, 1H, J=9.0 Hz),6.76-6.83 (m, 1H), 7.12 (dd, 1H, J=3.0, 12.0 Hz) 7.36 (t, 1H, J=9.0 Hz),7.60-7.70 (m, 1H), 9.45 (bs, 1H), 11.10 (bs, 1H), 11.24 (d, 1H, J=6.0Hz); ESI-MS m/z 627.5 (M⁺+2).

The following compounds were synthesized as shown in scheme 61

2-{4-[(R)-3-(2-bromo-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-1-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-oneas TFA salt (5b) was prepared from2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-piperidin-4-yl-1H-1,3,6-triaza-s-indacene-5,7-dionedihydrochloride and (R)-1-amino-3-(2-bromo-phenoxy)-propan-2-ol. ESI-MSm/z 593.5 (M⁺).

2-{4-[(R)-3-(2-bromo-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-ethyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-oneas TFA salt

(5c) was prepared from2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dionedihydrochloride and (R)-1-amino-3-(2-bromo-phenoxy)-propan-2-ol. ESI-MSm/z 623.0 (M⁺+2).

Synthesis of (R)-1-amino-3-(2-chloro-4-methoxy-phenoxy)-propan-2-ol

A mixture of 2-[(2R)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (1)(0.640 g, 3.15 mmol), 2-chloro-4-methoxyphenol (2) (0.500 g, 3.15 mmol),and DBU (25 μL, 0.16 mmol) in p-xylene was heated at 120° C. forthroughnight. The reaction mixture was cooled and then propan-2-ol (15mL) and hydrazine (600 μL, 18.9 mmol) were added. The resulting mixturewas heated at 90° C. for 5 h and cooled to room temperature. Thereaction was diluted with 1 N NaOH (30 mL) and extracted with ethylacetate (3×20 mL). The combined extract was washed with 1 N NaOH (25mL), dried through Na₂SO₄ and concentrated under reduced pressure to getcrude (R)-1-amino-3-(2-chloro-4-methoxyphenoxy)propan-2-ol (3a) (0.547g) which was used for next reaction without further purification. ESI-MSm/z 232.4 (M⁺+1).

The following amino alcohols were synthesized using the above procedureand designated phenol unless otherwise noted

(R)-1-amino-3-(2-chloro-4-fluoro-3-methylphenoxy)propan-2-ol (3b)

Yield: 0.567 g; ESI-MS m/z 233.9 (M⁺+1).

(R)-1-amino-3-(2-bromo-4,6-difluorophenoxy)propan-2-ol

Yield: 0.539 g; ESI-MS m/z 282.1 (M⁺) and 284.1 (M⁺+2).

(R)-1-amino-3-(2-(trifluoromethyl)phenoxy)propan-2-ol

Yield: 0.594 g; ESI-MS m/z 236.1 (M⁺+1).

(R)-1-amino-3-(2-chloro-5-fluorophenoxy)propan-2-ol

Yield: 0.584 g; ESI-MS m/z 219.9 (M⁺+1).

(R)-1-amino-3-(2-bromo-4-fluorophenoxy)propan-2-ol

Yield: 0.497 g; ESI-MS m/z 264.3 (M⁺) and 266.3 (M⁺+2).

(R)-1-amino-3-(2-bromo-4-methylphenoxy)propan-2-ol (3g)

Yield: 0.485 g; ESI-MS m/z 260.4 (M⁺) and 262.4 (M⁺+2).

(R)-1-amino-3-(2-chloro-5-(trifluoromethyl)phenoxy)propan-2-ol (3 h)

Yield: 0.500 g; ESI-MS m/z 270.0 (M++1).

(R)-1-amino-3-(2-bromophenoxy)propan-2-ol (3l)

Yield: 0.533 g; ESI-MS m/z 245.8 (M⁺) and 247.8 (M⁺+2).

(R)-1-amino-3-(2-bromo-4,5-difluorophenoxy)propan-2-ol (3j)

Yield: 0.472 g; ESI-MS m/z 282.4 (M⁺) and 284.4 (M⁺+2).

(R)-1-amino-3-(2-chloro-4,5-difluorophenoxy)propan-2-ol (3k)

Yield: 0.527 g; ESI-MS m/z 238.1 (M⁺+1).

(R)-1-amino-3-(2-chloro-6-fluorophenoxy)propan-2-ol (31)

Yield: 0.532 g; ESI-MS m/z 220.1 (M⁺+1).

(R)-1-amino-3-(2-chloro-6-fluorophenoxy)propan-2-ol (3 m)

Yield: 0.473 g; ESI-MS m/z 269.9 (M⁺+1).

(R)-1-amino-3-(2-chloro-6-fluorophenoxy)propan-2-ol (3n)

Yield: 0.519 g; ESI-MS m/z 238.4 (M⁺+1).

(R)-1-amino-3-[(6-ethyl-1,3-benzodioxol-5-yl)oxy]propan-2-ol (3o)

Yield: 0.503 g; ESI-MS m/z 239.9 (M⁺+1).

(R)-1-amino-3-[(6-chloro-1,3-benzodioxol-5-yl)oxy]propan-2-ol (3p)

Yield: 0.462 g; ESI-MS m/z 246.3 (M⁺+1).

(R)-1-amino-3-(6-chloro-2-fluoro-3-methylphenoxy)propan-2-ol (3q)

Yield: 0.516 g; ESI-MS m/z 234.3 (M⁺+1).

(R)-1-amino-3-(4-methyl-benzo[1,3]dioxol-5-yloxy)-propan-2-ol (3r)

Yield: 0.550 g; ESI-MS m/z 226.3 (M++1).

(R)-1-amino-3-(4-ethyl-benzo[1,3]dioxol-5-yloxy)-propan-2-ol (3s)

Yield: 0.400 g; ESI-MS m/z 240.2 (M⁺+1).

(R)-1-amino-3-(4-chloro-benzo[1,3]dioxol-5-yloxy)-propan-2-ol (3t)

Yield: 0.450 g; ESI-MS m/z 246.5 (M⁺+1).

(R)-1-amino-3-(4-fluoro-2,4-dimethyl-phenoxy)-propan-2-ol (3u)

Yield: 0.300 g; ESI-MS m/z 214.1 (M++1).

(R)-1-amino-3-(3-fluoro-2,4-dimethyl-phenoxy)-propan-2-ol (3u) (300 mg)was obtained from 2-[(2R)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione(1) (0.250 g, 1.78 mmol), and 3-fluoro-2,4-dimethyl-phenol (0.362 g,1.78 mmol) by application of the above methodology.

Synthesis of2-{4-[(R)-3-(2-chloro-4-methoxy-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

A mixture of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dionedihydrochloride (300 mg, 0.61 mmol),(R)-1-amino-3-(2-chloro-4-methoxyphenoxy)-propan-2-ol (175 mg, 0.80mmol) and Et₃N (375 mg, 3.71 mmol) in EtOH (4 mL) was heated at 100° C.for 12 h. The reaction mixture was cooled and concentrated under reducedpressure to dryness (700 mg). A portion of crude mixture (100 mg) wasmixed with zinc dust (250 mg) in AcOH (4 mL) and heated at 90° C. for 3h. The mixture was cooled, filtered through celite and solid was washedwith 1:1 MeOH/CH₂Cl₂ (5 mL). The filtrate was concentrated and theresidue was passed through small silica gel column (10% NH₄OH inMeOH/CH₂Cl₂ (1:9). Column fractions were concentrated and obtainedcompound was subjected to HPLC purification to afford2-{4-[(R)-3-(2-chloro-4-methoxy-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-oneas TFA salt (5a) (20 mg, 31.9%, 2 steps). ¹H NMR (DMSO-d₆) δ 1.80-2.15(m, 4H), 2.80 (s, 3H), 3.10-3.3 (m, 2H), 3.40-4.15 (m, 7H), 4.20-4.38(m, 1H), 4.45 (s, 2H), 6.22 (d, 1H, J=9.0 Hz), 6.86 (m, 1H), 7.08 (s,1H), 7.12 (d, 1H, J=9.0 Hz) 7.36 (t, 1H, J=9.0 Hz), 7.80 (m, 2H), 9.40(bs, 1H), 11.13 (bs, 1H), 11.24 (d, 1H, J=9.0 Hz); ESI-MS m/z 593.5(M⁺+1).

By application of the above methodology and using designated aminoalcohol, the following compounds were synthesized.

2-{4-[(R)-3-(2-chloro-5-fluoro-3-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (22 mg, 43%).; ¹H NMR (DMSO-d₆) δ 1.80-2.15 (m, 4H), 2.31 (s,3H), 2.80 (s, 3H), 3.10-3.90 (m, 6H), 4.00-4.18 (m, 3H), 4.22-4.37 (m,1H), 4.50 (s, 2H), 5.55 (bs, 1H), 6.21 (d, 1H, J=6.0 Hz), 7.05-7.25 (m,2H), 7.40 (t, 1H, J=6.0 Hz), 7.50-8.0 (m, 2H), 9.40 (bs, 1H), 11.10 (bs,1H), 11.23 (d, 1H, J=9.0 Hz); ESI-MS m/z 595.5 (M⁺+1).

2-{4-[(R)-3-(2,4-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (17 mg, 26%).; ¹H NMR (DMSO-d₆) δ 1.80-2.15 (m, 4H), 2.80 (s,3H), 3.05-3.30 (m, 2H) 3.40-3.95 (m, 4H), 4.0-4.18 (m, 3H), 4.21-4.38(m, 1H), 4.46 (s, 2H), 5.58 (bs, 1H), 6.21 (d, 1H, J=6.0 Hz), 6.90-7.0(m, 1H), 7.15-7.30 (m, 3H), 7.42-8.0 (m, 2H), 9.40 (bs, 1H), 11.12 (bs,1H), 11.23 (d, 1H, J=6.0 Hz); ESI-MS m/z 565.5 (M⁺+1).

2-{4-[(R)-3-(2-trifluoromethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (19 mg, 31%).; ¹H NMR (DMSO-d₆) δ 1.80-2.15 (m, 4H), 2.82 (s,3H), 3.1-3.35 (m, 2H) 3.40-3.95 (m, 4H), 4.0-4.40 (m, 4H), 4.46 (s, 2H),5.57 (bs, 1H), 6.18 (d, 1H, J=6.0 Hz), 7.0-7.33 (m, 1H), 7.34-7.59 (m,2H), 7.50-8.0 (m, 4H), 9.40 (bs, 1H), 11.14 (bs, 1H), 11.23 (d, 1H,J=3.0 Hz); ESI-MS m/z 597.2 (M⁺+1).

2-{4-[(R)-3-(2-chloro-5-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (18 mg, 27.9%); ¹H NMR (DMSO-d₆) δ 1.90-2.15 (m, 4H), 2.85 (s,3H), 3.10-3.30 (m, 2H) 3.40-3.95 (m, 4H), 4.08-4.18 (m, 3H), 4.25-4.40(m, 1H), 4.47 (s, 2H), 5.65 (bs, 1H), 6.22 (d, 1H, J=9.0 Hz), 6.84 (t,1H J=9.0 Hz), 7.15 (dd, 1H, J=9.0, 15.0 Hz), 7.31-7.34 (m, 1H),7.40-7.55 (m, 1H), 7.50-8.0 (m, 2H), 9.35 (bs, 1H), 11.13 (bs, 1H),11.24 (d, 1H, J=6.0 Hz); ESI-MS m/z 581.5 (M++1).

2-{4-[(R)-3-(2-chloro-5-trifluoromethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (15 mg, 23%); ¹H NMR (DMSO-d₆) δ 1.80-2.10 (m, 4H), 2.80 (s, 3H),3.10-3.28 (m, 2H) 3.40-3.95 (m, 4H), 4.08-4.35 (m, 4H), 4.47 (s, 2H),5.62 (bs, 1H), 6.21 (d, 1H, J=6.0 Hz), 7.28-7.40 (m, 2H), 7.50 (s, 1H),7.60-8.10 (m, 3H), 9.40 (bs, 1H), 11.13 (bs, 1H), 11.25 (bs, 1H); ESI-MSm/z 631.3 (M⁺+1).

2-{4-[(R)-3-(2-chloro-3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (21 mg, 28%); ¹H NMR (DMSO-d₆) δ 1.80-2.10 (m, 4H), 2.80 (s, 3H),3.10-3.80 (m, 4H), 4.08-4.20 (m, 3H), 4.21-4.40 (m, 1H), 4.49 (s, 2H),6.22 (d, 1H, J=6.0 Hz), 7.00-7.15 (m, 2H), 7.30-7.40 (m, 1H), 7.50-8.10(m, 2H), 9.35 (bs, 1H), 11.13 (bs, 1H), 11.24 (bs, 1H); ESI-MS m/z 599.5(M++1).

2-{4-[(R)-3-(2-chloro-6-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (20 mg, 32%).; ¹H NMR (DMSO-d₆) δ 1.85-2.12 (m, 4H), 2.81 (s,3H), 3.10-3.90 (m, 4H) 4.05-4.20 (m, 3H), 4.21-4.42 (m, 1H), 4.50 (s,2H), 5.55 (bs, 1H), 6.21 (d, 1H, J=6.0 Hz), 7.11-7.19 (m, 1H), 7.20-7.42(m, 3H), 7.50-8.05 (m, 2H), 9.41 (bs, 1H), 11.13 (bs, 1H), 11.24 (d, 1H,J=6.0 Hz); ESI-MS m/z 581.5 (M⁺+1)

2-{4-[(R)-3-(2-chloro-3-trifluoromethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (17 mg, 26%); ¹H NMR (DMSO-d₆) δ 1.80-2.10 (m, 4H), 2.81 (s, 3H),3.10-3.85 (m, 4H) 4.10-4.65 (m, 6H), 5.60 (bs, 1H), 6.24 (d, 1H, J=6.0Hz), 6.90-7.29 (m, 1H), 7.30-7.70 (m, 4H), 7.75-8.05 (m, 1H), 9.45 (bs,1H), 11.15 (bs, 1H), 11.24 (bs, 1H,); ESI-MS m/z 631.7 (M⁺+1).

2-{4-[(R)-3-(2-chloro-3,5-difluoromethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (20 mg, 30%); ¹H NMR (DMSO-d₆) δ 1.85-2.15 (m, 4H), 2.85 (s, 3H),3.10-3.85 (m, 4H), 4.00-4.18 (m, 1H), 4.20-4.40 (m, 4H), 4.49 (s, 2H),5.55 (bs, 1H), 6.22 (d, 1H, J=9.0 Hz), 7.10-7.29 (m, 1H), 7.30-7.45 (m,2H), 7.50-8.0 (m, 2H), 9.38 (bs, 1H), 11.12 (bs, 1H), 11.25 (d, 1H J=6.0Hz); ESI-MS m/z 599.7 (M⁺+1).

2-{4-[(R)-3-[(6-ethyl-1,3-benzodioxol-5-yl)oxy]-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (15 mg, 19%); ¹H NMR (DMSO-d₆) δ 1.10 (t, 3H, J=9.0 Hz),1.90-2.15 (m, 4H), 2.50 (q, 2H, J=9.0, 15.0 Hz) 2.82 (s, 3H), 3.10-3.25(m, 2H), 3.35-4.15 (m, 6H), 4.25-4.40 (m, 1H), 4.47 (s, 2H), 5.50 (bs,1H), 5.91 (s, 2H), 6.20 (d, 1H, J=6.0 Hz), 6.75 (s, 1H), 6.77 (s, 1H),7.34-7.39 (m, 1H), 7.50-8.0 (m, 2H), 9.38 (bs, 1H), 11.13 (bs, 1H),11.23 (d, 1H, J=6.0 Hz); ESI-MS m/z 601.5 (M⁺+1).

2-{4-[(R)-3-(6-chloro-benzo[1,3]dioxol-5-yloxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (14 mg, 22%).; ¹H NMR (DMSO-d₆) δ 1.80-2.13 (m, 4H), 2.81 (s,3H), 3.10-3.30 (m, 2H), 3.40-4.60 (m, 3H), 3.65-4.25 (m, 4H), 4.26-4.36(m, 1H), 4.50 (s, 2H), 5.50 (bs, 1H), 6.02 (s, 2H), 6.22 (d, 1H, J=9.0Hz), 6.98 (s, 1H), 7.10 (s, 1H), 7.36 (t, 1H, J=6.0 Hz), 7.50-7.95 (m,2H), 9.42 (bs, 1H), 11.11 (bs, 1H), 11.23 (d, 1H, J=6.0 Hz); ESI-MS m/z607.0 (M++1).

2-{4-[(R)-3-(2-chloro-6-fluoro-5-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (23 mg, 37%).; ¹H NMR (DMSO-d₆) δ 1.85-2.10 (m, 4H), 2.12 (s,3H), 2.81 (s, 3H), 3.10-3.25 (m, 2H) 3.40-3.65 (m, 3H), 3.74-3.80 (m,1H), 4.0-4.18 (m, 3H), 4.20-4.40 (m, 1H), 4.50 (s, 2H), 6.21 (d, 1H,J=6.0 Hz), 7.01-7.06 (m, 1H), 7.19-7.7.22 (m, 1H), 7.38 (m, 1H),7.60-8.0 (m, 2H), 9.44 (bs, 1H), 11.12 (bs, 1H), 11.24 (d, 1H J=9.0 Hz);ESI-MS m/z 595.7 (M⁺+1).

2-{4-[(R)-2-hydroxy-3-(4-methyl-benzo[1,3]dioxol-5-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (32 mg, 41%); ¹H NMR (DMSO-d₆) δ 1.82-2.10 (m, 4H), 2.20 (s, 3H),2.79 (s, 3H), 3.15-3.30 (m, 2H) 3.45-3.85 (m, 3H), 3.90-4.03 (m, 2H),4.10-4.20 (m, 1H), 4.25-4.40 (m, 1H), 4.50 (s, 2H), 6.00 (s, 2H), 6.20(d, 1H, J=9.0 Hz), 6.45 (d, 1H, J=9.0 Hz), 6.60 (d, 1H, J=9.0 Hz), 7.47(t, 1H, J=6.0 Hz), 7.65-8.0 (m, 2H), 9.50 (bs, 1H), 11.11 (bs, 1H),11.21 (d, 1H J=6.0 Hz); ESI-MS m/z 587.0 (M⁺+1).

2-{4-[(R)-2-hydroxy-3-(4-ethyl-benzo[1,3]dioxol-5-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

Yield: (30 mg, 36%); ¹H NMR (DMSO-d₆) δ 1.13 (t, 3H, J=9.0 Hz),1.87-2.18 (m, 4H), 2.58 (q, 2H, J=9.0, 15.0 Hz), 2.83 (s, 3H), 3.09-3.38(m, 2H) 3.43-4.20 (m, 7H), 4.23-4.30 (m, 1H), 4.48 (s, 2H), 5.42 (bs,1H), 5.98 (s, 2H), 6.21 (d, 1H, J=9.0 Hz), 6.39 (d, 1H, J=9.0 Hz), 6.58(d, 1H, J=9.0 Hz), 7.39 (t, 1H, J=6.0 Hz), 7.63-8.0 (m, 2H), 9.44 (bs,1H), 11.14 (bs, 1H), 11.20 (d, 1H, J=6.0 Hz); ESI-MS m/z 601.7 (M⁺+1).

Synthesis of2-{4-[(R)-3-(2-bromo-4,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

A mixture of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacene-5-onedihydrochloride (200 mg, 0.42 mmol),(R)-1-amino-3-(2-chloro-4-methoxyphenoxy)-propan-2-ol (150 mg, 0.53mmol) and Et₃N (420 μL, 2.9 mmol) in EtOH (3 mL) was heated at 100° C.for 12 h. The reaction mixture was cooled, concentrated and the obtainedresidue was subjected to HPLC purification to afford the2-{4-[(R)-3-(2-bromo-4,6-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (5p) (35 mg, 11%). ¹H NMR (DMSO-d₆) δ1.85-2.11 (m, 4H), 2.82 (s, 3H), 3.10-3.35 (m, 2H), 3.40-4.15 (m, 7H),4.18-4.35 (m, 1H), 4.45 (s, 2H), 5.55 (bs, 1H), 6.22 (d, 1H, J=9.0 Hz),7.30-7.55 (m, 3H) 7.60-8.10 (m, 2H), 9.40 (bs, 1H), 11.13 (bs, 1H),11.24 (d, 1H, J=9.0 Hz); ESI-MS m/z 643.5 (M⁺) and 645.5(M⁺+2).

The following compounds were synthesized using above procedure anddesignated amino alcohol.

2-{4-[(R)-3-(2-bromo-4-fluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(25 mg, 8.0%). ¹H NMR (DMSO-d₆) δ 1.80-2.10 (m, 4H), 2.80 (s, 3H),3.11-3.30 (m, 2H), 3.40-4.80 (m, 4H), 4.00-4.20 (m, 3H), 4.26-4.36 (m,1H), 4.50 (s, 2H), 5.55 (bs, 1H), 6.24 (d, 1H, J=6.0 Hz), 7.10-7.20 (m,2H), 7.21-7.39 (m, 1H), 7.58-9.7.82 (m, 1H), 7.85-8.0 (m, 2H), 9.45 (bs,1H), 11.10 (bs, 1H), 11.23 (d, 1H, J=6.0 Hz); ESI-MS m/z 627.3(M⁺+2).

2-{4-[(R)-3-(2-bromo-4-methyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(28 mg, 9.0%). ¹H NMR (DMSO-d₆) δ 1.90-2.10 (m, 4H), 2.25 (s, 3H), 2.80(s, 3H), 3.10-3.30 (m, 2H), 3.40-3.75 (m, 4H), 4.05-4.18 (m, 3H),4.20-4.40 (m, 1H), 4.55 (s, 2H), 5.50 (bs, 1H), 6.23 (d, 1H, J=9.0 Hz),6.98-7.29 (m, 2H) 7.36-7.48 (m, 2H), 7.58-7.82 (m, 1H), 7.75-7.96 (m,2H), 9.48 (bs, 1H), 11.11 (bs, 1H), 11.21 (d, 1H, J=6.0 Hz); ESI-MS m/z621.5 (M⁺).

2-{4-[(R)-3-(2-bromo-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(18 mg, 6.0%). ¹H NMR (DMSO-d₆) δ 1.82-2.08 (m, 4H), 2.79 (s, 3H),3.10-3.25 (m, 2H), 3.40-3.80 (m, 4H), 4.03-4.20 (m, 3H), 4.21-4.35 (m,1H), 4.55 (s, 2H), 5.50 (bs, 1H), 6.23 (d, 1H, J=6.0 Hz), 6.88-6.93 (m,1H), 7.06-7.16 (m, 1H), 7.29-7.37 (m, 2H), 7.54-7.61 (m, 1H), 7.70-8.0(m, 2H), 9.38 (bs, 1H), 11.12 (bs, 1H), 11.31 (d, 1H, J=6.0 Hz); ESI-MSm/z 607.5 (M⁺), 609.5 (M⁺+2).

2-{4-[(R)-3-(2-bromo-4,5-difluoro-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(30 mg, 9.3%). ¹H NMR (DMSO-d₆) δ 1.90-2.10 (m, 4H), 2.80 (s, 3H),3.10-3.30 (m, 2H), 3.40-3.80 (m, 4H), 4.00-4.20 (m, 3H), 4.22-4.40 (m,1H), 4.55 (s, 2H), 5.60 (bs, 1H), 6.23 (d, 1H, J=6.0 Hz), 7.25-7.50 (m,3H), 7.60-8.0 (m, 2H), 9.39 (bs, 1H), 11.12 (bs, 1H), 11.31 (d, 1H,J=6.0 Hz); ESI-MS m/z 643.5 (M⁺).

2-{4-[(R)-2-hydroxy-3-(4-chloro-benzo[1,3]dioxol-5-yloxy)-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(15 mg, 9.3%). ¹H NMR (DMSO-d₆) δ 1.90-2.10 (m, 4H), 2.79 (s, 3H),3.15-3.35 (m, 2H), 3.40-3.90 (m, 4H), 3.95-4.15 (m, 3H), 4.25-4.42 (m,1H), 4.47 (s, 2H), 5.55 (bs, 1H), 6.08 (s, 2H), 6.21 (d, 1H, J=9.0 Hz),6.54 (d, 1H, J=6.0 Hz), 6.79 (d, 1H, J=6.0 Hz), 7.37 (t, 1H, J=6.0 Hz),7.60-8.0 (m, 2H), 9.45 (bs, 1H), 11.11 (bs, 1H), 11.21 (d, 1H, J=6.0Hz); ESI-MS m/z 643.5 (M⁺).

2-{4-[(R)-3-(2-fluoro-2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt

(22 mg, 7.5%). ¹H NMR (DMSO-d₆) δ 1.85-2.08 (m, 4H), 2.13 (s, 3H), 2.16(s, 3H), 2.74 (s, 3H), 3.08-3.30 (m, 2H), 3.42-3.62 (m, 3H), 3.65-3.75(m, 1H), 3.90-4.10 (m, 3H), 4.22-4.35 (m, 1H), 4.48 (s, 2H), 5.55 (bs,1H), 6.22 (d, 1H, J=9.0 Hz), 6.73 (d, 1H, J=9.0 Hz), 7.01 (t, 1H, J=9.0Hz), 7.379 (t, 1H, J=6.0 Hz), 7.60-7.95 (m, 2H), 9.48 (bs, 1H), 11.12(bs, 1H), 11.23 (d, 1H, J=6.0 Hz); ESI-MS m/z 575.8 (M⁺+1).

Synthesis of 4-methyl-benzo[1,3]dioxol-5-ol

To a 0° C. cooled solution of benzo[1,3]dioxol-5-ol (1)(42.88 g, 310.52mmol) and diisopropyl ethylamine (75.0 g g, 584.7 mmol) indichloromethane (400 mL) was slowly added methoxymethyl chloride (50.0g, 621.04 mmol) and stirred at room temperature for throughnight. Thereaction mixture was washed with water (3×200 mL), 10% sodium hydroxide(100 mL) and then with water (100 mL). The organic layer was dried andconcentrated to give 5-methoxymethoxy-benzo[1,3]dioxole. (2) (43.0 g,74.3%) as an oil. ¹H NMR (CDCl₃) δ 3.39 (s, 3H), 5.07 (s, 2H), 5.89 (s,2H), 6.48 (dd, 1H, J=3.0 Hz, 9.0 Hz), 6.61 (d, 1H, J=3.0 Hz), 6.69 (d,1H, J=9.0 Hz).

Synthesis of 4-methyl-benzo[1,3]dioxol-5-ol: To a cooled (−78° C.)solution of 5-methoxymethoxy-benzo[1,3]dioxole (5.0 g, 27.35 mmol) inTHF (25 mL) was slowly added 2.5 M solution of n-BuLi in hexane andstirred at nitrogen atmosphere. After 30 minutes, dimethyl sulphate(6.90 g, 54.7 mmol) was added and then resulting mixture was allowed towarm to room temperature and stirred for 7 h. The reaction was dilutedwith water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layer was dried (Na₂SO₄) and concentrated under vacuum to getcrude product. The obtained product was dissolved in methanol (50 mL)and 0.5 mL conc. HCl and then heated at 50° C. for 2 h. The reaction wasconcentrated, dissolved in ethyl acetate (50 mL) and washed withsaturated sodium bicarbonate. The solvent was evaporated under vacuum togive crude product. Silica gel column chromatography (30% CH₂Cl₂/Hexane)gave 4-methyl-benzo[1,3]dioxol-5-ol (3a) (3.0 g, 72%). ¹H NMR (CDCl₃) δ2.13 (s, 3H), 4.60 (s, 1H), 5.95 (s, 2H), 6.25 (d, 1H, J=6.0 Hz), 6.52(d, 1H, J=6.0 Hz).

Synthesis of 4-ethyl-benzo[1,3]dioxol-5-ol

To a cooled (−78° C.) solution of 5-methoxymethoxy-benzo[1,3]dioxole(5.0 g, 27.35 mmol) in THF (25 mL) was slowly added 2.5 M solution ofn-BuLi in hexane and stirred at nitrogen atmosphere. After 30 minutes,diethyl sulphate (8.43 g, 54.7 mmol) was added and then resultingmixture was allowed to warm to room temperature and stirred for 7 h. Thereaction was diluted with water (50 mL) and extracted with ethyl acetate(2×50 mL). The organic layer was dried (Na₂SO₄) and concentrated undervacuum to get crude product. The obtained product was dissolved inmethanol (50 mL) and 0.5 mL conc. HCl and then heated at 50° C. for 2 h.The reaction was concentrated, dissolved in ethyl acetate (50 mL) andwashed with saturated sodium bicarbonate. The solvent was evaporatedunder vacuum to give crude product. Silica gel column chromatography(30% CH₂Cl₂/Hexane) gave 4-ethyl-benzo[1,3]dioxol-5-ol (3b) (2.8 g,61%). ¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=9.0 Hz), 2.62 (q, 2H, J=9.0, 15.0Hz) 4.45 (bs, 1H), 5.90 (s, 2H), 6.22 (d, 1H, J=6.0 Hz), 6.52 (d, 1H,J=6.0 Hz).

Synthesis of 4-chloro-benzo[1,3]dioxol-5-ol

To a cooled (−78° C.) solution of 5-methoxymethoxy-benzo[1,3]dioxole(5.0 g, 27.35 mmol) in THF (25 mL) was slowly added 2.5 M solution ofn-BuLi in hexane and stirred at nitrogen atmosphere. After 30 minutes, asolution of hexachloroethane (12.95 g, 54.7 mmol) in THF (25 mL) wasadded and then resulting mixture was allowed to warm to room temperatureand stirred for 7 h. The reaction was diluted with water (50 mL) andextracted with ethyl acetate (2×50 mL). The organic layer was dried(Na₂SO₄) and concentrated under vacuum to get crude product. Theobtained product was dissolved in methanol (50 mL) and 0.5 mL conc. HCland then heated at 50° C. for 2 h. The reaction was concentrated,dissolved in ethyl acetate (50 mL) and washed with saturated aqueoussodium bicarbonate. The solvent was evaporated under vacuum to givecrude product. Silica gel column chromatography (30% CH₂Cl₂/Hexane) gave4-chloro-benzo[1,3]dioxol-5-ol (3c) (2.5 g, 53%). ¹H NMR (CDCl₃) δ 5.12(s, 1H), 6.0 (s, 2H), 6.47 (d, 1H, J=9.0 Hz), 6.62 (d, 1H, J=9.0 Hz).

Synthesis of 3-fluoro-2,4-dimethylphenol

To a cooled (0° C.) solution of 2,2,6,6-tetramethylpiperidine (1.10 g,7.84 mmol) in THF (5 mL) was slowly added 2.5 M solution of n-BuLi inhexane (3.1 mL) and stirred for 15 minutes. The reaction mixture wascooled to −78° C. and then a solution of2-fluoro-4-methoxy-1-methyl-benzene(4) (1.0 g, 27.35 mmol) in THF (5 mL)was added. After stirring 20 minutes, methyl iodide (2.0 g 14.16 mmol)was added and the resulting mixture was allowed to warm to 0° C. througha period of 3 h. The reaction was diluted with 1 N HCl (15 mL) andextracted with ether (3×25 mL). The organic layer was dried (Na₂SO₄) anddistilled out to get crude product. The obtained product was dissolvedin dichloromethane (30 mL) and cooled to −78° C. Boron tribromide (4.0g, 15.9 mmol) was slowly added and then mixture was allowed to warm to0° C. After 5 h, the reaction was slowly poured in to ice water (25 mL)and extracted with dichloromethane (2×30 mL). The organic extracts weredried and solvent was evaporated at low temperature (20° C.) and vacuumto a residue. Flash column chromatography (30% CH₂Cl₂/Hexane) of thecrude product gave 3-fluoro-2,4-dimethyl-phenol (3d) (0.65 g, 65%). ¹HNMR (CDCl₃) δ 2.14 (s, 3H), 2.15 (s, 3H), 4.81 (s, 1H), 6.45 (d, 1H,J=9.0 Hz), 6.84 (t, 1H, J=9.0 Hz).

Synthesis of N-alkylated nitro-amino-phthalimide Synthesis5-Amino-6-nitro-2-(2-pyrrolidin-1-ylethyl)-1H-isoindole-1,3(2H)-dione

A mixture containing phthalimide (1; 2 g, 9.7 mmol, 1.0 eq.),2-pyrrolidin-1-ylethanamine (2a, 1.1 g, 9.7 mmol, 1.0 eq.) and imidazole0.17 g, 2.43 mmol, 0.25 eq.) in dioxane (40 mL) was heated in a cappedvial at 110° C. for 14 h. Additional 0.25 eq. of imidazole was added andreaction heated for 24 h. The mixture was cooled to room temperature andconcentrated in vacuo to a solid which was used as such in the nextstep.

The following compounds were prepared using either of the above methods.

Synthesis of Tricyclic Halopyridones2-(4-Iodo-2-methoxypyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

Pd/C (250 mg) was added to a solution of crude5-amino-6-nitro-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione inMeOH/AcOH (100 mL/5 mL) and hydrogenated for 5 h. The mixture wasfiltered through Celite and the filtrate was treated with4-iodo-2-methoxynicotinaldehyde (3.2 g, 12.07 mmol) and stirred atambient temperature open to air for 12 h and at 80° C. for 5 h. Thereaction mixture was cooled to ambient temperature and concentrated invacuo to dryness. Purification by flash chromatography gave the title5,6-diamino-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione as asolid (2.02 g, 32% through 4 steps). ¹H NMR (MeOD): δ 8.15 (s, 2H),8.01-8.08 (t, J=3 Hz 1H), 7.64 (t, J=3 Hz, 1H), 3.89-3.78 (m, 2H),3.41-3.22 (m, 2H), 2.95-2.81 (m, 6H), 2.15-1.82 (m, 7H). ESMS (m/z) 532(M+H)⁺.

2-(4-Halo-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionedihydrochloride

A mixture of conc. HCl (6 mL) and iodo-methoxypyridine derivative (1.97g, 33.7 mmol) in 45 mL of dioxane was stirred at ambient temperatureprotected from light for 30 h. THF (25 mL) was added to the reactionmixture and the solid was isolated by filtration, washed with Et₂O (4×15mL), dried at 45° C. in a vacuum oven to afford the title compound as alight chocolate colored solid (1.82 g). ¹H NMR (MeOH-d₄): δ 12.74 (br s,1H), 10.60 (br s, 1H), 8.14 (s, 2H), 7.73 (d, J=9 Hz, 1H), 6.65 (d, J=9Hz, 1H), 3.72-3.64 (m, 1H), 3.51-3.43 (m, 1H), 3.21-3.15 (m, 1H),2.99-2.93 (m, 1H), 2.07-1.82 (m, 3H). ESMS (m/z) 426.1 (M+H)⁺ for X═C1and 518.2 (M+H)⁺ for X=I.

Synthesis of Tricyclic Phthalimides

The above tricyclic phthalimides were prepared form the correspondingdiamines and 4-chloro-2-methoxypyridine-3-carboxaldehyde by applicationof the general procedure, such as A above, or B below.

Synthesis of 4-chloro-2-methoxypyridine-3-carboxaldehyde

2-Methoxy-nicotinonitrile

2-Methoxy-nicotinonitrile was prepared according to the literature byreaction of the 2-chloro-nicotinonitrile with MeONa in MeOH according toDunn, A. D.; Norrie, R.; Heterocycl. Chem.; EN; 24; 1987; 85-89.

4-Chloro-2-methoxy-nicotinonitrile (4-chloro-2-methoxy-3-cyanopyridine

The mixture of 210 mL of THF and 18 mL of diisopropylamine (0.13 mol),degassed with nitrogen gas in an ultrasonic bath and was cooled to −78°C. Then 1.6M BuLi (81 mL, 0.13 mol) was added dropwise. The mixture wasstirred at this temperature for 30 min, then cooled to −85° C. and asolution of 2-methoxy-nicotinonitrile (15.9 g, 0.119 mol) in 100 mL ofdegassed anhydrous THF was added dropwise. After 1 h of stirring at −80°C., a solution of hexachloroethane (56.9 g, 0.240 mol) in 200 mL of THFwas added causing the temperature to rise to −40° C. The cooling bathwas removed and stirred for 15 min. The reaction mixture was poured intowater and extracted with ethyl acetate (2×200 mL). The extract was driedthrough sodium sulfate, filtered through silicagel, and evaporated undervacuum. The resulting residue was purified by column chromatography(silicagel, EtOAc/hexane, 2:1) to give 89% of product. NMR ¹H (DMSO d₆,δ ppm): 8.44 (d, 1H 6-H, J=5.5 Hz); 7.42 (d, 1H, 5-H, J=5.5 Hz); 4.02(s, 3H, CH₃O).

4-Chloro-2-methoxy-pyridine-3-carbaldehyde(4-Chloro-2-methoxynicotinonitrile)

To the solution of the nitrile (2.0 g, 0.0118 mol) in 20 mL of THF wasadded 1.5M DIBAL in toluene (16 mL, 2.1 eq.) at room temperature. Thiscaused the temperature to rise to 40° C. The mixture is stirred for 1.5h and poured in portions into a solution of 3.5 mL of acetic acid in 50mL of water. After the gas evolution ceased, the mixture was extractedfirst with hexane/THF (1:1), then with ethyl acetate. The combinedextracts were dried through sodium sulfate, evaporated under vacuum; andthe residue was purified by column (silicagel, hexane/EtOAc) to give 900mg (44%) of the product. NMR ¹H (CDCl₃, 6 ppm): 10.30 (s. 1H, CHO); 8.34(d, 1H 6-H, J=5.6 Hz); 7.24 (d, 1H, 5-H, J=5.6 Hz); 3.99 (s, 3H, CH₃O).

Synthesis of Tricyclic Halopyridones

Step 1: NaH (2.05 g, 60 wt % dispersion in oil, 5.13 mmol, 1.06 eq.) wasadded portion wise to a solution of the phthalimide (10.0 g, 48.3 mmol,1.0 eq.) in degassed DMF (50 mL) and heated at 60° C. for 45 min. Themixture was cooled to room temperature and stirred throughnight. Then, asolution of dibromoethane (18.1 g, 96.6 mmol) in acetone (50 mL) wasadded drop wise. The cake was broken up and thick slurry was refluxedthroughnight. The reaction mixture was cooled to room temperature andfiltered. The filtrate was concentrated in vacuo to a residual oil. Thefilter cake was washed with MeOH and filtered into the residual oil.Additional MeOH was added and the yellow powder obtained was isolatedand washed with hexanes to afford 10.14 g (67%) of the desired product.The filtrate cake was taken up in EtOAc (100 mL) and washed with water(50 mL). The aqueous layer was back extracted with EtOAc (50 mL). Theorganic extracts were combined, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford a yellow solid (2.11 g, 14%) afterdrying in an oven under high vacuum. Throughall yield (12.26 g, 81%). ¹HNMR (DMSO-d₆) 8.45 (br s, 2H) 8.35 (s, 1H), 7.48 (s, 1H), 3.96 (t,J=6.33 Hz, 2H), 3.70 (t, J=6.33 Hz, 2H).

Step 2: A mixture of the bromophthalimide (1.0 g, 3.2 mmol), AcOH (10drops) in MeOH (15 mL) was hydrogenated at atmospheric pressure andambient temperature for 3 h. The mixture was filtered through Celite,Celite was washed well with MeOH, and the filtrate was concentrated invacuo to afford a residual solid (840 mg; 92%). ¹H NMR (CDCl₃) 7.11 (s,2H), 4.02 (t, J=6.72 Hz, 2H), 3.86 (br s, 4H), 3.57 (t, J=6.72 Hz, 2H)

Step 3: Aldehyde (508 mg, 2.96 mmol, 1.0 eq.) was added to aheterogeneous mixture of the diaminophthalimide (840 mg, 2.96 mmol, 1.0eq.) in MeOH/AcOH (3/1; 40 mL) and stirred at ambient temperature for 48h. The reaction mixture was concentrated in vacuo to a residual solidand purified by flash chromatography (R_(f)=0.30; 20% EtOAc/DCM) toisolate fractions corresponding to the desired product (1.25 g, 97%, 84%pure). ¹H NMR (CDCl₃) 10.90 (br s, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.15 (d,J=5.5 Hz, 1H), 4.15 (t, J=6.7 Hz, 2H), 3.65 (t, J=6.7 Hz, 2H). ESMS(m/z) 435.

Step 4: Bromoethylphthalimide (1 eq.) and the secondary amine (3.0 eq.)[Note: 1.2 eq. of powdered K₂CO₃ was added if secondary amine was HClsalts) in degassed, anhydrous DMF (0.13 M solution) and heated in cappedvial at 75-80° C. for 6-48 h. The desired products were purified byflash chromatography to afford products as shown below.

Analytical data for2-(4-Chloro-2-methoxypyridin-3-yl)-6-{2-[(2S)-2-methylpyrrolidin-1-yl]ethyl}imidazo[4,5-f]isoindole-5,7(1H,6H)-dione.

¹H NMR (CDCl₃) 8.28 (br s, 1H), 8.17 (d, J=5.5 Hz, 1H), 8.02 (br s, 1H),7.14 (d, J=5.5 Hz, 1H), 4.01 (s, 3H), 3.41-3.09 (m, 2H), 2.47-2.19 (m,3H), 1.91-1.78 (m, 1H), 1.65-1.52 (m, 1H), 1.45-1.29 (m, 1H), 1.25 (brs, 1H), 1.19-1.17 (m, 1H), 1.03 (d, J=3.3 Hz, 3H) 0.91-0.72 (m, 1H).ESMS (m/z) 440.91.

Analytical data for2-(4-Chloro-2-methoxypyridin-3-yl)-6-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]imidazo[4,5-f]isoindole-5,7(1H,6H)-dione.

¹H NMR (MeOH-d₄) 8.32 (d, J=5.6 Hz, 1H), 8.14 (s, 2H), 7.29 (d, J=5.6Hz, 1H), 4.05-3.94 (m, 5H), 3.53-3.37 (m, 4H), 3.29-3.10 (m, 6H). ESMS(m/z) 490.3.

Step 5: The crude product from Step 4 above was dissolved in dioxane/conHCl (5/1) and stirred at ambient temperature throughnight. The reactionmixture was concentrated in vacuo to dryness, azeotroped with EtOH (2×)to obtain the corresponding monoHCl salts as a powder. These were usedin the next steps as such.

Synthesis of Lactam Containing Chloropyridones

Step 1: Tin powder (1.96 g, 16.5 mmol, 10.0 eq.) was added to a solutionof nitro-aminophthalimide derivative[5-amino-2-(substituted)-6-nitroisoindoline-1,3-dione] (550 mg, 1.65mmol) in EtOH (7 mL)/con HCl (1.7 mL) and refluxed for 24 h. Anotherbatch of tin powder (1.96 g, 16.5 mmol) and con Hcl (1.7 mL) were addedand reflux continued for 15 h. The reaction mixture was decanted toremove tin, and concentrated in vacuo to a residue. The residue wasdissolved in MeOH and conc. aq. NH₄OH was added until no moreprecipitation was observed. The reaction mixture was filtered and silicagel was added to the filtrate and concentrated in vacuo. The residue wasadsorbed on silica gel and purified by flash chromatography [10% (5% aq.NH₄OH/MeOH)/DCM; RF0.32] to afford the desired product as a thick yellowoil (314 mg, 66%).

Step 2: A solution of the aldehyde (189 mg, 1.1 mmol, 1.0 eq.) in MeOH(10 mL) was added drop wise to a 0-5° C. solution of the lactam (0.31 g,1.1 mmol; from step 1) in MeOH (10 mL) and stirred at room temperaturefor 14 h and at 50° C. for 1 d. The reaction mixture was filteredthrough Celite, and the filtrate was concentrated in vacuo to a residueand purified by flash chromatography [10% (5% aq. NH₄OH/MeOH)/DCM;R_(f)=0.40) to isolate fractions corresponding to the desired product.The isolated product was used as such in the next step.

Step 3: Con HCl (0.8 mL) was added to a solution of the product fromstep 2 (225 mg, 0.51 mmol) in dioxane (3 mL) and stirred at ambienttemperature throughnight and at 60° C. for 2 h. The reaction mixture wasconcentrated in vacuo to dryness to afford 279 mg of the desired productas a grey solid. ESMS (m/z) 426.4. This was used as such in the nextsteps.

In a similar fashion was synthesized2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

Synthesis of Aryloxypropanolamine Containing Phthalimides2-(4-{[(2R)-3-(2,4-dimethylphenoxy)-2-hydroxypropyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

(2R)-1-amino-3-(2,4-dimethylphenoxy)propan-2-ol (75 mg, 0.38 mmol, 1.2eq.) was added to a solution of the halo-pyridone (150 mg, 0.32 mmol,1.0 eq.) and Et₃N (150 μL, 1.05 mmol, 3.3 eq.) and heated at 100° C. for2 h and stirred at ambient temperature throughnight. The reactionmixture was filtered and the solid was dried in a vacuum oven at 40° C.throughnight to afford the title compound as a tan colored powder (87mg, 47%). ¹H NMR (DMSO-d₆): δ 13.42 (s, 1H), 11.31 (br s, 1H), 10.97 (t,J=5.3 Hz, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.39 (d, J=5.7 Hz, 1H), 6.97(s, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 6.22 (d, J=7.5Hz, 1H), 5.55 (d, J=5.1 Hz, 1H), 4.11-3.85 (m, 3H), 3.80-3.51 (m, 3H),3.16 (d, J=4.5 Hz, 2H), 3.21-2.56 (m, 4H), 2.21 (s, 3H), 2.19 (s, 3H),1.91-1.78 (m, 2H), 1.65 (br s, 3H), 1.46-0.99 (m, 2H). ESMS (m/z) 585.5(M+H)⁺

2-(4-{[(2R)-3-(2,4-dimethylphenoxy)-2-hydroxypropyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

Prepared by application of the above methodology.

Purified by HPLC; Yield 26%; ESMS (m/z) 571.5

Synthesis of Aryloxypropanolamine Containing Lactams2-(4-{[(2R)-3-(2-Ethyl-4-methylphenoxy)-2-hydroxypropyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one

Zn (246 mg, 3.8 g atoms, 23.3 eq.) was added to a solution of thephthalimide derivative (95 mg, 0.163 mmol) in glacial acetic acid (˜2mL) and heated at 120° C. (bath) for 2 h. Reaction mixture was cooled toambient temperature and the mixture was filtered through Celite. Celite,washed with MeOH (3×10 mL) and the filtrate was concentrated in vacuoand azeotroped with toluene (3×15 mL). Flash chromatography purificationof the resultant residue [10% (5% aq. NH₄OH/MeOH)/DCM] afforded thedesired compound as a cream solid (41 mg, 44%). R_(f)0.40; more polar ofthe two UV and fluorescent spots of the crude material. ¹H NMR(DMSO-d₆): δ 12.62 (s, 1H), 11.27 (br s, 1H), 11.06 and 10.75 (brsinglets, 1H), 7.93 and 7.87 (s, 1H), 7.1629 (br s, 1H), 6.99-6.92 (m,1H), 6.76 (d, J=7.1 Hz, 1H), 6.07 (br s, 1H), 4.55-4.35 (m, 2H),4.18-4.07 (m, 2H), 3.80-3.51 (m, 2H), 3.21-3.05 (br s, 2H), 2.71-2.59(m, 2H), 2.58-2.38 (m, 5H), 2.29-2.59 (m, 4H), 2.40-1.98 (m, 5H),1.98-1.78 (m, 3H), 1.31-1.05 (m, 3H). ESMS (m/z) 571.5 (M+H)⁺.

The following were prepared by application of the above methodology:

2-(4-{[(2R)-3-(2,4-Dimethylphenoxy)-2-hydroxypropyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(46a) ESMS (m/z) 557.5 (M+H⁺); Yield (48%); purity 100%

Prepared by Zn/AcOH reduction outlined above.

(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-(pyrrolidin-1-yl)propyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

The O-acetate was also formed in the reaction:

Chlorinated Compounds

The synthesis of the above presented compounds is described in Scheme78.

5-Amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione

5-Amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione:A suspension of5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (3.04 g,10 mmol) in HOAc (100 mL) was bubbled with Cl₂ gas for 5.5 h andevaporated to dryness. The residue was diluted with aqueous MeOH (25 mL,80%) and basified with aqueous NH₄OH solution (28%) resulting a solutionto which NaHSO₃ (10.4 g, 100 mmol) was added. The mixture was sonicatedfor 30 min and loaded on silica gel. Chromatography of the mixture withmixed solvent of CH₂Cl₂/MeOH/28% aqueous NH₄OH (20:10:1) afforded thetitle compound which is not pure, but was used for the next stepreaction directly without further purification.

5,6-Diamino-4-chloro-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione

5,6-Diamino-4-chloro-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione: Toa mixture of5-amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione(1.35 g, not pure) and 10% Pd/C (500 mg) was added 2-propanol (20 mL),HCl in dioxane (4 M, 0.1 mL) and then MeOH (230 mL). After it wasstirred under atmospheric hydrogen for 1.5 h, the reaction mixture wasfiltered over Celite. The filtrate was concentrated, diluted with 50%DCM in MeOH, basified with aqueous NH₄OH solution (28%) and evaporated.Chromatography of the mixture with mixed solvent of CH₂Cl₂/MeOH/28%aqueous NH₄OH (50:10:1) afforded the title compound (186 mg, 6% for 2steps). ¹H NMR (DMSO-d₆) δ 1.51 (m, 2H), 1.90 (m, 2H), 2.29 (m, 2H),2.81 (m, 2H), 3.80 (m, 1H), 5.61 (br s, 2H, NH₂), 5.93 (br s, 2H, NH₂),6.82 (s, 1H, ArH); ESI-MS m/z 309.4 (MH⁺).

4-Chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

4-Chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:A solution of5,6-diamino-4-chloro-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione(62.0 mg, 0.2 mmol), 4-iodo-2-methoxynicotinic aldehyde (34.3 mg, 0.2mmol) and HOAc (1 mL) in MeOH was stirred at the room temperature for 14h, heated at 80° C. for 4.5 h, and concentrated to result a residuewhich was then mixed with HCl in dioxane (4 M, 10 mL) and H₂O (0.8 mL)and heated for 1.7 h at 70° C. for 1.5 h. The reaction mixture wasevaporated, diluted with diluted with a mixed solvent of DCM/MeOH (1:5),basified with aqueous NH₄OH solution (28%) and evaporated.Chromatography of the residue with mixed solvent of CH₂Cl₂/MeOH/28%aqueous NH₄OH (40:10:1) afforded the title compound (70.2 mg, 78% for 2steps). ESI-MS m/z 446.5 (MH⁺).

4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:A solution of4-chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(18 mg, 0.04 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol(12.0 mg, 0.06 mmol) and Et₃N (0.2 mL, 1.43 mmol) in EtOH (2.0 mL) washeated at 100° C. for 19 h and then concentrated to result a residuewhich was subjected to HPLC purification to furnish the title compoundin TFA salt form (3.98 mg, 14%). ¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.15(s, 3H), 2.19 (s, 3H), 2.51 (m, 2H), 2.80 (s, 3H), 3.18 (m, 2H),3.50-3.80 (4H), 4.02 (m, 2H), 4.15 (m, 1H), 4.30 (m, 1H), 5.50 (br s,1H, NH), 6.25 (d, J=8 Hz, 1H), 6.80-6.94 (3H), 7.40 (m, 1H), 8.08 (s,1H), 9.49 (br s, 1H), 10.90 (br s, 1H), 11.36 (d, J=6 Hz, 1H); ESI-MSm/z 605.3 (MH⁺).

8-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

8-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(50.1 mg, 0.083 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) inHOAc (15 mL). After it was heated at 90° C. for 1 h, the reactionmixture was cooled to 50° C. and diluted with a mixed solvent ofMeOH:DCM (45 mL/5 mL) and filtered. The filtrate was evaporated at 95°C. (the bath temperature) under reduced pressure to dryness. The residuewas diluted with a mixed solvent of DCM/MeOH (1:5) and basified with 28%aqueous NH₄OH solution and concentrated. Chromatography of the residualcrude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (16:10:1) followed by HPLCre-purification afforded the title compound in TFA salt form (9.23 mg,19%). ¹H NMR (DMSO-d₆) δ 1.95-2.12 (4H), 2.16 (s, 3H, CH₃), 2.19 (s, 3H,CH₃), 2.80 (s, 3H, CH₃), 3.19 (m, 2H), 3.50-3.75 (4H), 4.07 (m, 2H),4.12 (m, 1H), 4.30 (s, 1H), 4.49 (s, 2H), 6.22 (m, 1H), 6.80-6.95 (3H),7.40 (1H), 7.95 (s, 1H), 9.64 (br s, 1H), 11.02 (br s, H, NH), 11.29 (brs, 1H, NH); ESI-MS m/z 591.3 (MH⁺).

Synthesis of Sulfone, Sulfoxide and Sulfide Derivatives

4-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione

4-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione(2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g,12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed ina ChemGlass heavy wall pressure flask. After it was heated at 140° C.for 72 h, the reaction mixture was evaporated to dryness at 95° C. (thebath temperature) under reduced pressure. The chromatography of theresidue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (320:10:1) afforded the titlecompound (2.09 g, 54%). ¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.73 (m, 2H),2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34(s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a mixture of4-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (5.0 g, 12.8 mmol) and 10% Pd/C (500 mg) was added2-propanol (20 mL), and then MeOH (230 mL). After it was stirred underatmospheric hydrogen for 4 h, the reaction mixture was filtered overCelite. The filtrate was mixed with 4-iodo-2-methoxynicotinic aldehyde(3.37 g, 12.8 mmol) and HOAc (13 mL), stirred at the room temperaturefor 16 h, and evaporated under reduced pressure to afford an oil crudewhich was mixed with HCl in dioxane (4 M, 60 mL) and H₂O (5 mL), heatedat 70° C. for 1.5 h and evaporated at 95° C. (the bath temperature) todryness. Et₃N (5.35 mL, 38.4 mmol) was added to the solution of theresidue in DCM (250 mL) at 0° C. under N₂ and followed by the additionof the solution of Boc₂O (3.35 g, 15.4 mmol). After it was stirred at 0°C. for 1 h and at the room temperature for 19 h, the reaction mixturewas mixed slowly with MeOH (200 mL) at 0° C. and then evaporated at 70°C. (the both temperature) to dryness under reduced pressure. The residuewas mixed with (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (2.5 g,12.8 mmol) and Et₃N (5.35 mL, 38.4 mmol) in EtOH (200 mL) resulting amixture which was heated at 100° C. for 5 h and then concentrated.Chromatography of the residual mixture with CH₂Cl₂/MeOH/28% aqueousNH₄OH (250:10:1) furnished a fluorescent product which was mixed withzinc dust (5.5 g, 84 mmol) and HOAc (200 mL). After it was heated to 90°C. for 2 h, the reaction mixture was filtered and the filtrate wasconcentrated at 70° C. (the both temperature) under reduced pressure.The residue was mixed with HCl in dioxane (4 M, 60 mL) and H₂O (5 mL),heated at 70° C. for 2.5 h and evaporated at 95° C. (the bathtemperature) to dryness. The residue was basified with NH₃ in EtOH (2 M)and concentrated. Chromatography of the crude with CH₂Cl₂/MeOH/28%aqueous NH₄OH (40:10:1) afforded a fluorescent product (6.5 g). 50 mg ofthis product was subjected to HPLC purification to furnish the titlecompound in TFA salt form (37 mg). ¹H NMR (DMSO-d₆) δ 1.90-2.05 (4H),2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 3.13 (m, 2H), 3.42 (m, 2H), 3.55(m, 1H), 3.69 (m, 1H), 4.03 (m, 2H), 4.13 (m, 1H), 4.39 (m, 1H), 4.46(s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz,1H), 6.98 (s, 1H), 7.39 (d, J=7 Hz, 1H), 7.55 (br s, 1H), 7.85 (br s,1H), 11.14 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z543.5 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:A mixture of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(3.04 g, 5.6 mmol) and methyl vinyl sulfone (5.94 g, 56 mmol) in a mixedsolvent of EtOH (70.0 mL) and 2-propanol (70.0 mL) was heated at 100° C.for 22 h and then evaporated. Chromatography of the residue withCH₂Cl₂/MeOH/28% aqueous NH₄OH (190:10:1) afforded title compound (2.82g, 78%). ¹H NMR (DMSO-d₆) δ 1.68-1.85 (4H), 2.15 (m, 2H), 2.18 (s, 3H,CH₃), 2.21 (s, 3H, CH₃), 2.75 (m, 2H), 3.05 (m, 2H), 3.08 (s, 3H, CH₃),3.54 (m, 1H), 3.70 (m, 1H), 3.93-4.19 (4H), 4.43 (s, 1H), 4.47 (s, 1H),5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H),6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.67 (s, 0.5H), 7.80 (s,0.5H), 7.94 (s, 0.5H), 11.14 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6Hz, 1H, NH); ESI-MS m/z 649.5 (MH⁺); Anal. Calcd for C₃₃H₄₀N₆O₆S: C,61.09; H, 6.21; N, 12.95, S 4.94; Found: C, 60.85; H, 6.17; N, 12.87, S4.85.

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-ethanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-ethanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:This compound was prepared by application of the above methodology. ¹HNMR (DMSO-d₆) δ 1.23 (t, J=6 Hz, 3H, CH₃), 1.65-1.82 (4H), 2.15 (m, 2H),2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.76 (m, 2H), 3.02 (m, 2H), 3.17(q, J=6 Hz, 2H), 3.29 (m, 2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.93-4.18(4H), 4.43 (s, 1H), 4.48 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.54 (d,J=6 Hz, 0.5H, NH), 6.20 (m, 1H), 6.81 (m, 1H), 6.89-6.98 (2H), 7.30-7.38(1.5H), 7.67 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (br d, J=6Hz, 1H, NH), 11.20 (br s, 1H, NH); ESI-MS m/z 663.7 (MH⁺).

Acetic acid1-(2,4-dimethyl-phenoxymethyl)-2-(3-{6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-7-oxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl}-2-oxo-1,2-dihydro-pyridin-4-ylamino)-ethylester

Acetic acid1-(2,4-dimethyl-phenoxymethyl)-2-(3-{6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-7-oxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl}-2-oxo-1,2-dihydro-pyridin-4-ylamino)-ethylester: A solution of2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(65 mg, 0.1 mmol) in HOAc (20 mL) was refluxed for 32 h and wasevaporated. The residue was diluted with a mixed solvent of DCM/MeOH(1:5), basified with 28% aqueous NH₄OH solution and concentrated.Chromatography of the residual crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH(110:10:1) followed by HPLC re-purification afforded the title compoundin TFA salt form (8.69 mg, 11%). ¹H NMR (DMSO-d₆) δ 1.99-2.12 (4H), 2.05(s, 3H, CH₃), 2.16 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 3.15 (s, 3H, CH₃),3.25 (m, 2H), 3.52 (m, 2H), 3.60-3.78 (5H), 3.90 (s, 1H), 4.10-4.38(4H), 4.49 (br s, 2H), 5.43 (br s, 2H, NH), 6.28 (d, J=8 Hz, 1H), 6.84(d, J=6 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 6.99 (s, 1H), 7.40 (m, 1H), 7.80(br s, 1H), 9.80 (br s, 1H), 11.14 (br s, NH), 11.33 (br d, J=6 Hz, 1H,NH); ESI-MS m/z 691.7 (MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methylsulfanyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methylsulfanyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:A mixture of the2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(542 mg, 1.0 mmol), 1-chloro-2-methylsulfanyl-ethane (122 mg, 1.1 mmol),Na₂CO₃ (318 mg, 3.0 mmol) and NaI (150 mg, 1.0 mmol) in CH₃CN (20 mL)was heated at 100° C. for 22 h and then evaporated. Chromatography ofthe residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (200:10:1) afforded thetitle compound. ¹H NMR (DMSO-d₆) δ 1.69-1.82 (4H), 2.09 (s, 3H, CH₃),2.09 (m, 2H), 2.19 (s, 3H, CH₃), 2.20 (s, 3H, CH₃), 2.50-2.59 (4H), 3.00(m, 2H), 3.38 (m, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.98-4.08 (3H), 4.15(m, 1H), 4.43 (s, 11H), 4.47 (s, 1H), 5.47 (br s, 0.5H, NH), 5.53 (br s,0.5H, NH), 6.20 (m, 1H), 6.80-6.99 (3H), 7.30-7.36 (1.5H), 7.68 (s,0.5H), 7.79 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (br d, J=6 Hz, 1H, NH),11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 617.5 (MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfinyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfinyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one: To a solution of2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methylsulfanyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(333 mg, 0.5 mmol) in HOAc (10 mL) was added H₂O₂ (30% in H₂O, 1 mL).After it was stirred at the room temperature for 1 h, the reactionmixture was cooled down to 0° C. and diluted with aqueous MeOH (50%, 90mL) resulting a solution to which NaHSO₃ (5.2 g, 50 mmol) was added. Thereaction mixture was evaporated after it was stirred at 0° C. for 1 hand the residue was diluted with a mixed solvent of DCM/MeOH (1:5),basified with 28% aqueous NH₄OH solution and concentrated.Chromatography of the residual crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH(110:10:1) afforded the title compound (242 mg, 71%). ¹H NMR (DMSO-d₆)1.69-1.85 (4H), 2.10 (m, 2H), 2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.55(s, 3H, CH₃), 2.60-2.81 (2H), 3.00 (m, 2H), 3.38 (m, 2H), 3.54 (m, 1H),3.70 (m, 1H), 3.98-4.08 (3H), 4.15 (m, 1H), 4.43 (s, 1H), 4.48 (s, 1H),5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H),6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.68 (s, 0.5H), 7.80 (s,0.5H), 7.94 (s, 0.5H), 11.15 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6Hz, 1H, NH); ESI-MS m/z 633.5 (MH⁺).

Synthesis of Additional Sulfones

[2-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-methyl-carbamicacid tert-butyl ester

[2-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-methyl-carbamicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione(2.07 g, 10 mmol), (2-Amino-ethyl)-methyl-carbamic acid tert-butyl ester(3.485 g, 20 mmol), imidazole (1.36 g, 20 mmol) in dioxane (30 mL) wassealed in a ChemGlass heavy wall pressure flask. After it was heated at140° C. for 38 h, the reaction mixture was evaporated to dryness at 95°C. (the bath temperature) under reduced pressure. The chromatography ofthe residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (500:10:1) afforded thetitle compound (3.39 g, 93%). ¹H NMR (CDCl₃) δ 1.08 (s, 9H), 2.78 (s,3H), 3.42 (m, 2H), 3.68 (m, 2H), 7.48 (s, 1H), 8.34 (s, 1H), 8.42 (br s,2H, NH).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-1H-1,3,6-triaza-s-indacene-5,7-dione

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-1H-1,3,6-triaza-s-indacene-5,7-dione:A mixture of[2-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-methyl-carbamicacid tert-butyl ester (729 mg, 2.0 mmol) and TFA (7 mL) in DCM (28 mL)was stirred at the room temperature for 5 h and evaporated to dryness toresult a residue which was diluted with a mixed solvent of DCM/MeOH(1:5), basified with 28% aqueous NH₄OH solution and evaporated. Theresidue was mixed with methyl vinyl ketone (1.27 g, 12 mmol) in a mixedsolvent of ethanol (10 mL) and isopropanol (10 mL), heated at 100° C.for 38 h, cooled to the room temperature, diluted with a solution ofHOAc in MeOH (5%, 100 mL). The mixture was mixed with Pd/C (100 mg) andstirred under atmospheric H₂ for 2.5 h and filtered through Celite. Thefiltrate was mixed with 4-chloro-2-methoxynicotinic aldehyde (377.5 mg,2.2 mmol), stirred at the room temperature for 140 h, and evaporatedunder reduced pressure to afford an oil crude which was mixed with HClin dioxane (4 M, 25 mL) and H₂O (2 mL), heated at 60° C. for 30 min andevaporated at 95° C. (the bath temperature) to a crude product. 1/20 ofthis crude product of was mixed with(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (29.3 mg, 0.15 mmol)and Et₃N (0.3 mL, 2.1 mmol) in EtOH (2 mL) resulting a mixture which washeated at 100° C. for 5 h and then concentrated. Chromatography of theresidual mixture with CH₂Cl₂/MeOH/28% aqueous NH₄OH (150:10:1) furnishedthe title compound (42.4 mg, 27% for 6 steps). ¹H NMR (DMSO-d₆) δ 2.19(s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.64 (s, 3H, CH₃), 2.60 (m, 2H), 2.79(m, 2H), 2.90 (s, 3H, CH₃), 3.20 (m, 2H), 3.48 (m, 1H), 3.65-3.75 (3H),3.99 (m, 2H), 4.13 (m, 1H), 5.54 (d, J=6 Hz, 1H, NH), 6.23 (d, J=7 Hz,1H), 6.83 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.97 (s, 1H), 7.41 (m,1H), 7.67 (s, 1H), 8.12 (s, 1H), 10.97 (br s, 1H, NH), 11.29 (br d, J=6Hz, 1H, NH); ESI-MS m/z 637.7 (MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-1H-1,3,6-triaza-s-indacene-5,7-dione(35 mg, 0.055 mmol) was mixed with zinc dust (196 mg, 3 mmol) and HOAc(15 mL). After it was refluxed for 30 min, the reaction mixture wasfiltered and the filtrate was concentrated at 70° C. (the bathtemperature) under reduced pressure resulting a residue which wasdiluted with a mixed solvent of DCM/MeOH (10 mL:90 mL), basified with28% aqueous NH₄OH and concentrated. Chromatography of the crude residuewith CH₂Cl₂/MeOH/28% aqueous NH₄OH (190:10:1) afforded a fluorescentproduct (6.98 mg, 20%). ¹H NMR (DMSO-d₆) δ 2.13 (s, 3H, CH₃), 2.16 (s,3H, CH₃), 2.22 (s, 3H, CH₃), 2.65 (m, 2H), 2.80 (m, 2H), 2.85 (s, 3H,CH₃), 3.27 (m, 2H), 3.53 (m, 1H), 3.60-3.71 (3H), 4.02 (m, 2H), 4.13 (m,1H), 4.48 (s, 1H), 4.53 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d,J=6 Hz, 0.5H, NH), 6.22 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H), 6.89-6.99(2H), 7.30-7.35 (1.5H), 7.67 (s, 0.5H), 7.79 (s, 0.5H), 7.94 (s, 0.5H),11.15 (br m, 1H, NH); ESI-MS m/z 623.5 (MH⁺).

[2-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-methyl-carbamicacid tert-butyl ester

[2-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-methyl-carbamicacid tert-butyl ester: ¹H NMR (CDCl₃) δ 1.30 (s, 9H), 1.75 (m, 2H), 2.72(s, 3H), 3.12 (m, 2H), 3.49 (m, 2H), 7.40 (s, 1H), 8.29 (s, 1H), 8.41(br s, 2H, NH).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{3-[(2-methanesulfonyl-ethyl)-methyl-amino]-propyl}-1H-1,3,6-triaza-s-indacene-5,7-dione

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{3-[(2-methanesulfonyl-ethyl)-methyl-amino]-propyl}-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 1.75 (m, 2H), 2.19 (s, 3H, CH₃), 2.21 (s, 3H, CH₃),2.22 (s, 3H, CH₃), 2.39 (m, 2H), 2.75 (m, 2H), 3.01 (s, 3H, CH₃), 3.23(m, 2H), 3.60 (m, 2H), 3.75 (m, 2H), 3.99 (m, 2H), 4.13 (m, 1H), 5.54(d, J=6 Hz, 1H, NH), 6.23 (d, J=7 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 6.92(d, J=7 Hz, 1H), 6.97 (s, 1H), 7.41 (m, 1H), 7.67 (s, 1H), 8.12 (s, 1H),10.95 (br s, 1H, NH), 11.29 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 651.5(MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{3-[(2-methanesulfonyl-ethyl)-methyl-amino]-propyl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{3-[(2-methanesulfonyl-ethyl)-methyl-amino]-propyl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:¹H NMR (DMSO-d₆) δ 1.76 (m, 2H), 2.19 (s, 3H, CH₃), 2.20 (s, 3H, CH₃),2.21 (s, 3H, CH₃), 2.39 (m, 2H), 2.72 (m, 2H), 3.03 (s, 3H, CH₃), 3.29(m, 2H), 3.55 (m, 1H), 3.67 (m, 1H), 3.82 (m, 1H), 4.00 (m, 2H), 4.12(m, 1H), 4.46 (s, 1H), 4.50 (s, 1H), 5.48 (br s, 0.5H, NH), 5.52 (br s,0.5H, NH), 6.22 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H), 6.89-6.99 (2H),7.32-7.37 (1.5H), 7.67 (s, 0.5H), 7.79 (s, 0.5H), 7.94 (s, 0.5H), 11.15(br m, 1H, NH); ESI-MS m/z 637.7 (MH⁺).

Synthesis of Lactams with Pyrrolidinylethyl or Pyrrolidinylpropyl

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-{3-[(2-methanesulfonyl-ethyl)-methyl-amino]-propyl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

Synthesis of Methylated Lactams

R′¹ and R′² are hydrogen or methyl

Synthesis of Nitro-aminophthalimide derivative:(S)-5-amino-2-(1-(dimethylamino)propan-2-yl)-6-nitroisoindoline-1,3-dione

(1-Dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester

(1-Dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester: To asolution of DMAP (10 mg, 0.08 mmol) and DIEA (6.07 g, 47 mmol) in DCM(60 mL) was added a solution of dimethylamine in THF (2.0 M, 25.7 mL,51.3 mmol) and the mixture was stirred at 0° C. for 30 min. HOBt (6.35g, 47 mmol) was added to a solution of N-α-tert-Boc-L-alanine (8.09 g,42.76 mmol) in DCM (60 mL) and the mixture was stirred at 0° C. for 25min. The two solutions were combined into one solution to which EDCI(9.03 g, 47 mmol) was added and the reaction mixture was stirred at 0°C. for 1 h, stirred at the room temperature for 48 h and concentrated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(240:10:1) afforded the title compound (7.95 g, 86%). ¹H NMR (CDCl₃) δ1.30 (d, J=6 Hz, 3H, CH₃), 1.44 (s, 9H) 2.97 (s, 3H, CH₃), 3.06 (s, 3H,CH₃), 4.62 (q, J=6 Hz, 1H), 5.51 (d, J=6 Hz, 1H, NH).

2-Amino-N,N-dimethyl-propionamide: A solution of(1-dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester

2-Amino-N,N-dimethyl-propionamide: A solution of(1-dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (7.95 g) in20% TFA/DCM (200 mL) was stirred at the room temperature for 2 h andevaporated to result in a residue which was diluted with a mixed solventof MeOH/DCM (100 mL/100 mL), basified with 28% aqueous NH₄OH, andconcentrated. Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (90:10:1) afforded the title compound (3.49 g, 81%). ¹H NMR(MeOH-d₄) δ 1.28 (d, J=6 Hz, 3H, CH₃), 2.95 (s, 3H, CH₃), 3.08 (s, 3H,CH₃), 4.04 (q, J=6 Hz, 1H); ESI-MS m/z 117.3 (MH⁺).

HCl Salt of 2-amino-N,N-dimethyl-propylamine

HCl salt of 2-amino-N,N-dimethyl-propylamine: To a solution of2-amino-N,N-dimethyl-propionamide (3.49 g, 30 mmol) in THF (100 mL) wasadded BH₃-THF complex in THF (1.0 M, 90 mL, 90 mmol) at 0° C. resultingin a mixture which was stirred at the room temperature for 1 h andrefluxed under N₂ for 18 h. After it was cooled to 0° C., the reactionmixture was quenched by adding MeOH (20 mL) slowly and dropwise at 0° C.and then stirred for 16 h. Aqueous HCl (12 N, 6 mL) was added into thereaction mixture which was then heated at 80° C. for 1 h and evaporateto afford the title compound in HCl salt form (5.3 g) which was used forthe next step without purification. ¹H NMR (DMSO-d₆) δ 1.31 (d, J=6 Hz,3H, CH₃), 2.85 (s, 6H, 2CH₃), 3.32 (m, 1H), 3.48 (m, 1H), 3.80 (m, 1H),8.79 (br s, 2H, NH).

5-Amino-2-(2-dimethylamino-1-methyl-ethyl)-6-nitro-isoindole-1,3-dione:A mixture of 5-amino-6-nitro-isoindole-1,3-dione

5-Amino-2-(2-dimethylamino-1-methyl-ethyl)-6-nitro-isoindole-1,3-dione:A mixture of 5-amino-6-nitro-isoindole-1,3-dione (1.66 g, 8.0 mmol), HClsalt of 2-amino-N,N-dimethyl-propylamine (5.3 g, crude, <30 mmol),imidazole (1.36 g, 20 mmol) and Et₃N (8.4 mL, 6.07 g, 60 mmol) indioxane (80 mL) was sealed in a ChemGlass heavy wall pressure flask.After it was heated at 130° C. for 72 h, the reaction mixture wasevaporated to dryness at 95° C. (the bath temperature) under reducedpressure. The chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (240:10:1) afforded the title compound (1.49 g, 64%). ¹H NMR(DMSO-d₆) δ 1.32 (d, J=6 Hz, 3H, CH₃), 2.09 (s, 6H, 2CH₃), 2.25 (m, 1H),2.95 (m, 1H), 4.35 (m, 1H), 7.43 (s, 1H), 8.29 (s, 1H), 8.39 (br s, 2H,NH). ESI-MS m/z 293.1 (MH⁺).

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2-dimethylamino-1-methyl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2-dimethylamino-1-methyl-ethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:The mixture of5-amino-2-(2-dimethylamino-1-methyl-ethyl)-6-nitro-isoindole-1,3-dione(585 mg, 2.0 mmol) and Pd/C (60 mg) in MeOH (95 mL) was stirred underatmospheric H₂ for 2.5 h and filtered through Celite. The filtrate wasmixed with 4-chloro-2-methoxynicotinic aldehyde (343.2 mg, 2.0 mmol) andHOAc (5 mL), stirred at the room temperature for 62 h, and evaporatedunder reduced pressure to afford an oil crude which was mixed with HClin dioxane (4 M, 25 mL) and H₂O (2 mL), heated at 70° C. for 1 h andevaporated. The residue was diluted with a mixed solvent of MeOH/DCM (50mL/50 mL), basified with 28% aqueous NH₄OH, and concentrated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(60:10:1) afforded the title compound (642 mg, 80%). ¹H NMR (DMSO-d₆) δ1.39 (d, J=6 Hz, 3H, CH₃), 2.14 (s, 6H, 2CH₃), 2.29 (m, 1H), 3.04 (m,1H), 4.40 (m, 1H), 6.59 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 8.04 (s,1H), 8.05 (s, 1H); ESI-MS m/z 400.3 (MH⁺).

Synthesis of Nitroaminophthalimide

2-Dimethylamino-propionamide

2-Dimethylamino-propionamide: A mixture of H-Ala-NH₂—HCl (7.47 g, 60mmol), HCHO (37%, 14.6 mL) and Pd/C (750 mg) in MeOH (200 mL) wasstirred under atmospheric H₂ for 16 h and filtered through Celite. Thefiltrate was evaporated, diluted with a mixed solvent of MeOH/DCM (150mL/150 mL), basified with 28% aqueous NH₄OH, and concentrated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(60:10:1) afforded the title compound (6.43 g, 92%). ¹H NMR (DMSO-d₆) δ1.06 (d, J=8 Hz, 3H, CH₃), 2.16 (s, 6H, 2CH₃), 2.83 (q, J=8 Hz, 3H,CH₃), 6.94 (br s, 1H, NH), 7.18 (br s, 1H, NH); ESI-MS m/z 117.3 (MH⁺).

HCl Salt of 2-dimethylamino-propylamine

HCl salt of 2-dimethylamino-propylamine: To a solution of2-dimethylamino-propionamide (3.49 g, 30 mmol) in THF (100 mL) was addedBH₃-THF complex in THF (1.0 M, 90 mL, 90 mmol) at 0° C. resulting in amixture which was stirred at the room temperature for 1 h and refluxedunder N₂ for 22 h. After it was cooled to 0° C., the reaction mixturewas quenched by adding MeOH (25 mL) slowly and dropwise at 0° C. andthen stirred for 16 h. Aqueous HCl (12 N, 6 mL) was added into thereaction mixture which was then heated at 80° C. for 1 h and evaporateto afford the title compound in HCl salt form (5.5 g) which was used forthe next step without purification. ¹H NMR (DMSO-d₆) δ 1.06 (d, J=8 Hz,3H, CH₃), 2.75 (s, 6H, 2CH₃), 3.40 (m, 1H), 3.60-3.76 (2H), 8.81 (br s,2H).

5-Amino-2-(2-dimethylamino-propyl)-6-nitro-isoindole-1,3-dione

5-Amino-2-(2-dimethylamino-propyl)-6-nitro-isoindole-1,3-dione: Amixture of 5-amino-6-nitro-isoindole-1,3-dione (1.66 g, 8.0 mmol), HClsalt of 2-dimethylamino-propylamine (5.5 g, crude, <30 mmol), imidazole(1.36 g, 20 mmol) and Et₃N (8.4 mL, 6.07 g, 60 mmol) in dioxane (80 mL)was sealed in a ChemGlass heavy wall pressure flask. After it was heatedat 130° C. for 69 h, the reaction mixture was evaporated to dryness at95° C. (the bath temperature) under reduced pressure. The chromatographyof the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (240:10:1) affordedthe title compound (360 mg, 15%). ¹H NMR (DMSO-d₆) δ 0.88 (d, J=6 Hz,3H, CH₃), 2.13 (s, 6H, 2CH₃), 3.32 (m, 2H), 3.65 (m, 1H), 7.45 (s, 1H),8.30 (s, 1H), 8.40 (br s, 2H, NH). ESI-MS m/z 293.3 (MH⁺).2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2-dimethylamino-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2-dimethylamino-propyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:The mixture of5-amino-2-(2-dimethylamino-1-methyl-ethyl)-6-nitro-isoindole-1,3-dione(360 mg, 1.2 mmol) and Pd/C (40 mg) in MeOH (95 mL) was stirred underatmospheric H₂ for 24 h and filtered through Celite. The filtrate wasmixed with 4-chloro-2-methoxynicotinic aldehyde (343.2 mg, 2.0 mmol) andHOAc (5 mL), stirred at the room temperature for 96 h, and evaporatedunder reduced pressure to afford an oil crude which was mixed with HClin dioxane (4 M, 25 mL) and H₂O (2 mL), heated at 70° C. for 4 h andevaporated. The residue was diluted with a mixed solvent of MeOH/DCM (50mL/50 mL), basified with 28% aqueous NH₄OH, and concentrated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(60:10:1) afforded the title compound (281 mg, 58%). ¹H NMR (DMSO-d₆) δ0.95 (d, J=6 Hz, 3H, CH₃), 2.24 (s, 6H, 2CH₃), 3.10 (m, 1H), 3.45 (m,1H), 3.74 (m, 1H), 6.57 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 8.06 (s,1H), 8.07 (s, 1H); ESI-MS m/z 400.3 (MH⁺).

Synthesis of Azetidine-substitutedImidazo[4,5-f]isoindole-5,7(1H,6H)-dione Compounds

3-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-azetidine-1-carboxylicacid tert-butyl ester

3-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-azetidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione(994 mg, 4.8 mmol), 3-Aminomethyl-azetidine-1-carboxylic acid tert-butylester (1.0 g, 5.4 mmol) and imidazole (493 mg, 7.25 mmol) in dioxane(140 mL) was sealed in a ChemGlass heavy wall pressure flask. After itwas heated at 140° C. for 61 h, the reaction mixture was evaporated todryness at 95° C. (the bath temperature) under reduced pressure. Thechromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(400:10:1) afforded the title compound (830 mg, 46%). ¹H NMR (MeOH-d₄) δ1.44 (s, 9H), 2.94 (m, 1H), 3.78 (m, 2H), 3.88 (d, J=6 Hz, 2H), 4.00 (m,2H), 7.44 (s, 1H), 8.52 (s, 1H); ESI-MS m/z 377.3 (MH⁺).

2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-azetidin-3-ylmethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a mixture of3-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-azetidine-1-carboxylicacid tert-butyl ester (830 mg, 2.2 mmol) and 10% Pd/C (85 mg) was added2-propanol (10 mL), and then MeOH (90 mL). After it was stirred underatmospheric hydrogen for 4 h, the reaction mixture was filtered overCelite. The filtrate was mixed with 4-iodo-2-methoxynicotinic aldehyde(580 g, 2.2 mmol) and HOAc (5.0 mL), stirred at the room temperature for18 h, and evaporated under reduced pressure to afford an oil crude whichwas mixed with HCl in dioxane (4 M, 30 mL) and H₂O (2.5 mL), heated at70° C. for 2.5 h and evaporated at 95° C. (the bath temperature) todryness. The residue was diluted with a mixed solvent of DCM/MeOH (30mL/70 mL), basified with 28% aqueous NH₄OH and concentrated.Chromatography of the crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (25:10:1)afforded a crude product which was mixed with HOAc (2.1 mL) and HCHO(37% in H₂O, 2.1 mL) in a mixed solvent of MeOH/THF (24 mL/24 mL). Theresulting reaction mixture was stirred at the room temperature for 10min and followed by addition of Na(OAc)₃BH (2.54 g, 12.0 mmol). Thereaction mixture was stirred at the room temperature for 63 h and thenevaporated. Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (90:10:1) afforded the title compound (330 mg, 38%). ESI-MS m/z398.3 (MH⁺).

TFA salt of2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-azetidin-3-ylmethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione

TFA salt of2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-azetidin-3-ylmethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione:To a solution of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-azetidin-3-ylmethyl)-1H-1,3,6-triaza-s-indacene-5,7-dione(40 mg, 0.1 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol(20 mg, 0.1 mmol) in EtOH (2 mL) was added Et₃N (200 μL, 1.43 mmol).After it was heated at 95° C. for 22.5 h, the reaction mixture wasconcentrated under reduced pressure. HPLC purification of the residueafforded the title compound in TFA salt form (6.61 mg, 20%). ¹H NMR(DMSO-d₆) δ 2.19 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 2.82 (s, 3H, CH₃),3.09 (m, 1H), 3.59 (m, 1H), 3.70 (m, 1H), 3.83 (m, 2H), 3.90-4.18 (7H),5.55 (m, 1H, NH), 6.23 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 6.92 (d,J=8 Hz, 1H), 6.98 (s, 1H), 7.41 (m, 1H), 7.67 (s, 1H), 8.13 (s, 1H),9.83 (br s, 1H, NH), 10.95 (br s, 1H, NH), 11.30 (d, J=6 Hz, 1H); ESI-MSm/z 557.5 (MH⁺).

TFA Salt of2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-azetidin-3-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

TFA salt of2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-azetidin-3-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:¹H NMR (DMSO-d₆) δ 2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 3.00 (s, 3H,CH₃), 3.50-3.69 (3H), 3.95-4.29 (4H), 4.53 (m, 2H), 6.26 (d, J=8 Hz,1H), 6.84 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.98 (s, 1H), 7.41 (m,1H), 7.72 (br s, 1H), 8.17 (s, 1H), 10.94 (br s, 1H, NH), 11.31 (d, J=6Hz, 1H); ESI-MS m/z 543.2 (MH⁺).

Subthesis of Lactams with Variety of Amine Side Chains

Synthesis of Lactams

TFA salt of(R)-2-(4-(3-(2-chloro-3,6-difluoro-4-methoxyphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one:¹H NMR (DMSO-d₆) δ 1.95 (m, 2H), 2.20 (m, 2H), 2.75 (s, 3H, CH₃), 3.20(m, 2H), 3.50 (m, 2H), 3.75 (m, 1H), 3.85 (s, 3H, CH₃), 4.12 (m, 2H),4.35 (m, 1H), 4.50 (s, 2H), 6.22 (d, J=6 Hz, 1H), 7.31 (m, 1H), 7.39 (m,1H), 7.70 (s, 1H), 7.88 (s, 1H), 10.65 (br s, 1H), 11.04 (br s, 1H, NH),11.27 (d, J=6 Hz, 1H); ESI-MS m/z 629.5 (MH⁺).

Synthesis of Substituted LactamsSubstituted-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-ones

4-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione

4-(5-Amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester: A mixture of 5-amino-6-nitro-isoindole-1,3-dione(2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g,12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed ina ChemGlass heavy wall pressure flask. After it was heated at 140° C.for 72 h, the reaction mixture was evaporated to dryness at 95° C. (thebath temperature) under reduced pressure. The chromatography of theresidue with CH₂Cl₂/MeOH/28% aqueous NH₄OH (320:10:1) afforded the titlecompound (2.09 g, 54%). ¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.73 (m, 2H),2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34(s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH⁺).

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a mixture of4-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (5.0 g, 12.8 mmol) and 10% Pd/C (500 mg) was added2-propanol (20 mL), and then MeOH (230 mL). After it was stirred underatmospheric hydrogen for 4 h, the reaction mixture was filtered overCelite. The filtrate was mixed with 4-iodo-2-methoxynicotinic aldehyde(3.37 g, 12.8 mmol) and HOAc (13 mL), stirred at the room temperaturefor 16 h, and evaporated under reduced pressure to afford an oil crudewhich was mixed with HCl in dioxane (4 M, 60 mL) and H₂O (5 mL), heatedat 70° C. for 1.5 h and evaporated at 95° C. (the bath temperature) todryness. Et₃N (5.35 mL, 38.4 mmol) was added to the solution of theresidue in DCM (250 mL) at 0° C. under N₂ and followed by the additionof the solution of Boc₂O (3.35 g, 15.4 mmol) in a minimum amount of DCM.After it was stirred at 0° C. for 1 h and at the room temperature for 19h, the reaction mixture was mixed slowly with MeOH (200 mL) at 0° C. andthen evaporated at 70° C. (the bath temperature) to dryness underreduced pressure. The residue was mixed with(R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (2.5 g, 12.8 mmol) andEt₃N (5.35 mL, 38.4 mmol) in EtOH (200 mL) resulting in a mixture whichwas heated at 100° C. for 5 h and then concentrated. Chromatography ofthe residual mixture with CH₂Cl₂/MeOH/28% aqueous NH₄OH (250:10:1)furnished a fluorescent product which was mixed with zinc dust (5.5 g,84 mmol) and HOAc (200 mL). After it was heated to 90° C. for 2 h, thereaction mixture was filtered and the filtrate was concentrated at 70°C. (the bath temperature) under reduced pressure. The residue was mixedwith HCl in dioxane (4 M, 66 mL) and H₂O (5 mL), heated at 70° C. for2.5 h and evaporated at 95° C. (the bath temperature) to dryness. Theresidue was basified with NH₃ in EtOH (2 M) and concentrated.Chromatography of the crude with CH₂Cl₂/MeOH/28% aqueous NH₄OH (40:10:1)afforded a fluorescent product (6.5 g). 50 mg of this product wassubjected to HPLC purification to furnish the title compound in TFA saltform (37 mg). ¹H NMR (DMSO-d₆) δ 1.90-2.05 (4H), 2.19 (s, 3H, CH₃), 2.22(s, 3H, CH₃), 3.13 (m, 2H), 3.42 (m, 2H), 3.55 (m, 1H), 3.69 (m, 1H),4.03 (m, 2H), 4.13 (m, 1H), 4.39 (m, 1H), 4.46 (s, 2H), 6.22 (d, J=7 Hz,1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.39 (d,J=7 Hz, 1H), 7.55 (br s, 1H), 7.85 (br s, 1H), 11.14 (br s, 1H, NH),11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 543.5 (MH⁺).

TFA Salt of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(3-oxo-butyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

TFA salt of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(3-oxo-butyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:A mixture of2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(54.3 mg, 1 mmol) and methyl vinyl ketone (415 μL, 5.0 mmol) in DMF (1mL) was stirred at the room temperature for 17 h and the reactionmixture was subjected to HPLC purification to afford the title compoundin TFA salt form (30.4 mg, 40%). ¹H NMR (DMSO-d₆) δ 1.95 (2H), 2.10 (m,2H), 2.18 (s, 3H, CH₃), 2.21 (s, 3H, CH₃), 3.05 (m, 2H), 3.19 (m, 2H),3.26 (m, 2H), 3.50-3.61 (3H), 3.71 (m, 1H), 4.00 (m, 2H), 4.12 (m, 1H),4.35 (m, 1H), 4.45 (s, 2H), 6.23 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H),6.93 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.38 (dd, J=7 Hz and 7 Hz, 1H), 7.55(br s, 1H), 7.85 (br s, 1H), 9.79 (br s, 1H), 11.14 (br s, 1H, NH),11.25 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 613.5 (MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-propyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-propyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a solution of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(27.1 mg, 0.05 mmol) and propionaldehyde (150 μL) in a mixed solvent ofCH₃CN (6 mL) and H₂O (2 mL) was added HOAc (500 μL) at 0° C. and theresulting reaction mixture was stirred at 0° C. for 20 min and followedby addition of Na(OAc)₃BH (254 mg, 1.2 mmol). The reaction mixture wasstirred at 0° C. for 1 h and at the room temperature for 1 h and thenevaporated. Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (490:10:1) afforded the title compound (16.5 mg, 57%). ¹H NMR(DMSO-d₆) δ 0.87 (t, J=6 Hz, 3H, CH₃), 1.45 (m, 2H), 1.70 (m, 2H), 1.80(m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH₃), 2.22 (s, 3H, CH₃), 2.97 (m,2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s,1H), 4.47 (s, 1H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H,NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68(s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH),11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH⁺).

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-isopropyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

2-{4-[3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-isopropyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:A mixture of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(27.1 mg, 0.05 mmol), acetone (200 μL) and Ti(i-PrO)₄ (300 μL) wasstirred at the room temperature for 2 h and diluted with MeOH (5 mL).NaBH₄ (190 mg, 5 mmol) was added into the reaction mixture and themixture was stirred at the room temperature for 16 h and concentrated.Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueous NH₄OH(490:10:1) afforded the title compound (2.06 mg, 7%). ¹H NMR (DMSO-d₆) δ1.22 (s, 3H, CH₃), 1.24 (s, 3H, CH₃), 1.25-1.45 (4H), 1.80-2.30 (6H),3.33-3.60 (2H), 3.70 (m, 1H), 3.90-4.19 (2H), 4.35-4.50 (2H), 5.47 (m,1H, NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H),7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.18 (br s, 1H, NH),11.22 (d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH⁺).

6-(1-Cyclopropyl-piperidin-4-yl)-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

6-(1-Cyclopropyl-piperidin-4-yl)-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a solution of2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(54.3 mg, 0.1 mmol) and bromocyclopropane (121 mg, 1.0 mmol) in CH₃CN (8mL) was added DIEA (129.3 mg, 1.0 mmol) and the resulting reactionmixture was stirred at the room temperature for 112 h and thenevaporated. Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (490:10:1) afforded the title compound (3.27 mg, 5.6%). ¹H NMR(DMSO-d₆) δ 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH₃),2.22 (s, 3H, CH₃), 2.90-3.00 (4H), 3.45 (m, 1H), 3.70 (m, 1H), 3.95-4.06(3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.10-5.22 (2H), 5.47 (d,J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 5.81 (m, 1H), 6.22 (m,1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H),7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d,J=6 Hz, 1H, NH); ESI-MS m/z 583.7 (MH⁺).

Synthesis of other Tricyclic Derivatives

TFA salt of acetic acid1-(2,4-dimethyl-phenoxymethyl)-2-{3-[6-(1-methyl-piperidin-4-yl)-7-oxo-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-2-oxo-1,2-dihydro-pyridin-4-ylamino}-ethylester: A solution of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(30 mg, 0.054 mmol) in HOAc (4 mL0 was heated at 100° C. for 88 h andevaporated. The residue was subjected to HPLC purification to afford thetitle compound in TFA salt form (17.0 mg, 44%). ¹H NMR (DMSO-d₆) δ1.90-2.15 (4H), 2.05 (s, 3H, CH₃), 2.16 (s, 3H, CH₃), 2.22 (s, 3H, CH₃),2.81 (s, 3H, CH₃), 3.20 (m, 2H), 3.52 (m, 2H), 3.78 (m, 1H), 3.90 (m,1H), 4.20 (m, 2H), 4.31 (m, 1H), 4.47 (s, 2H), 5.43 (br s, 1H, NH), 6.28(d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.99 (s,1H), 7.41 (m, 1H), 7.60 (br s, 1H), 7.85 (br s, 1H), 9.60 (br s, 1H,NH), 11.13 (br s, 1H, NH), 11.33 (d, J=6 Hz, 1H); ESI-MS m/z 599.5(MH⁺).

Synthesis of4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-3-[6-(1-methyl-piperidin-4-yl)-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-1H-pyridin-2-one

TFA salt of4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-3-[6-(1-methyl-piperidin-4-yl)-1,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-2-yl]-1H-pyridin-2-one:To a suspension of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(20 mg, 0.036 mmol) in THF (3 mL) was added BH₃—S(CH₃)₂complex in ether(2.0 M, 2 mL, 4 mmol) at 0° C. resulting in a mixture which was stirredat the room temperature for 1 h and heated at 80° C. for 2 h. After itwas cooled to 0° C., the reaction mixture was quenched by adding MeOH (5mL) slowly and dropwise at 0° C. and then stirred for 16 h. Aqueous HCl(12 N, 2 mL) was added into the reaction mixture which was then heatedat 80° C. for 1 h and evaporated. The residue was diluted with a mixedsolvent of DCM/MeOH (10 mL/10 mL), basified with 28% aqueous NH₄OH, andconcentrated. Chromatography of the residue with CH₂Cl₂/MeOH/28% aqueousNH₄OH (110:10:1) furnished a crude product which was subjected to HPLCre-purification to afford the title compound in TFA salt form (1.67 mg,7%). ¹H NMR (DMSO-d₆) δ 1.85-2.00 (4H), 2.16 (s, 3H, CH₃), 2.22 (s, 3H,CH₃), 2.81 (s, 3H, CH₃), 3.10 (m, 2H), 3.52 (m, 2H), 3.78-4.11 (6H),4.62 (s, 2H), 4.85 (s, 2H), 5.43 (br s, 1H, NH), 6.19 (d, J=8 Hz, 1H),6.80 (d, J=8 Hz, 1H), 6.89-6.95 (2H), 7.32 (m, 1H), 7.45 (br s, 1H),7.55 (br s, 1H), 9.95 (br s, 1H, NH), 11.00 (br s, 1H, NH), 11.20 (br s,1H); ESI-MS m/z 543.5 (MH⁺).

TFA salt of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-methoxy-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:To a suspension of2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one(19 mg, 0.034 mmol) in a mixed solvent of THF/CH₃CN (1 mL/1 mL) wasadded a solution of TMSCH₂N₂ (2.0 M, 2 mL, 4 mmol) at 0° C. After it wasstirred at 0° C. for 2 h, the reaction mixture was mixed with MeOH (1mL), stirred at the room temperature for 22 h, and purified with apreparative TLC plate to furnish a crude which was subjected to HPLCre-purification to afford the title compound in TFA salt form (4.98 mg,21%). ¹H NMR (DMSO-d₆) δ 1.92-2.10 (4H), 2.19 (s, 3H, CH₃), 2.22 (s, 3H,CH₃), 2.81 (s, 3H, CH₃), 3.20 (m, 2H), 3.40 (s, 3H, OCH₃), 3.45-3.55(3H), 3.68 (m, 1H), 4.00 (s, 2H), 4.12 (m, 1H), 4.30 (m, 1H), 4.43 (s,1H), 4.48 (s, 1H), 5.47 (br s, 1H, NH), 6.27 (d, J=6 Hz, 1H), 6.82 (d,J=8 Hz, 1H), 6.89-6.97 (2H), 6.98 (s, 1H), 7.15 (s, 0.5H), 7.30 (s,0.5H), 7.65-7.72 (1.5H), 7.80 (s, 0.5H), 7.95 (s, 0.5H), 9.65 (br s, 1H,NH), 11.11 (br s, 1H, NH); ESI-MS m/z 571.5 (MH⁺).

Synthesis of (S)-2-amino-1-(3-chlorophenyl)ethanol derivatives

4-Iodo-2-methoxynicotinic aldehyde

4-Iodo-2-methoxynicotinic aldehyde: To a solution of t-BuLi (1.7 M, 7.36mL, 12.51 mmol) in 20 mL THF at −78° C. was added dropwise2-bromomesitylene (0.91 mL, 5.95 mmol). After stirred for 1 h,2-methoxypyridine (0.48 mL, 4.58 mmol) was added dropwise, and themixture was warmed to 0° C. and stirred for 2 h. The solution was cooledto −78° C. and N-formyl-N,N′,N′-trimethylethylenediamine (0.7 mL, 5.06mmol) was added. The mixture was stirred at −78° C. for 30 min and thenwarmed to −23° C. A hexane solution of n-BuLi (2.5 M, 2.75 mL, 6.87mmol) was added dropwise, and the resulting yellow mixture was stirredfor 3 h. The mixture was cooled to −78° C. and transferred via adouble-tipped needle to a solution of iodine (2.17 g, 8.23 mmol) in 30mL of THF at −78° C. After stirred at −78° C. for 30 min, the coolingbath was removed and the reaction mixture was allowed to warm to theroom temperature. After the reaction mixture was cooled to −5° C.,aqueous solution of NH₄Cl (20 mL) was added dropwise and stirred for 15min. The reaction mixture was poured into brine (300 mL) and extractedwith EtOAc (5×100 mL). The combined extracts were washed with brine(2×50 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography (25:1 hexanes/EtOAc) to afford the title compound (350mg, 29%). ¹H NMR (CDCl₃) δ 4.05 (s, 3H, CH₃), 7.53 (d, J=6 Hz, 1H, ArH),7.85 (d, J=6 Hz, 1H, ArH), 10.20 (s, 1H, CHO).

3-[1,3] Dioxolan-2-yl-4-iodo-2-methoxy-pyridine

3-[1,3]Dioxolan-2-yl-4-iodo-2-methoxy-pyridine: To a solution of4-iodo-2-methoxynicotinic aldehyde (5.26 g, 20.0 mmol) and ethyleneglycol (2.48 g, 40 mmol) in toluene (400 mL) was added p-toluenesulfonicacid monohydrate (95 mg, 0.5 mmol). After it was refluxed under N₂ for 6h, the reaction mixture was concentrated and the residue was dilutedwith 300 mL EtOAc and washed with 2×100 mL 10% Na₂CO₃ solution. Theaqueous solution was extracted with EtOAc (3×50 mL) and the combinedEtOAc extracts were washed with brine and dried over Na₂SO₄. Evaporationof solvent afforded the title product (6.07 g, 99%). ¹H NMR (CDCl₃) δ3.95 (s, 3H), 4.07 (m, 2H), 4.33 (m, 2H), 6.25 (s, 1H), 7.40 (d, J=6 Hz,1H), 7.70 (d, J=6 Hz, 1H). ESI-MS m/z 308.4 (MH⁺).

(S)-1-(3-Chloro-phenyl)-2-(3-[1,3]dioxolan-2-yl-2-methoxy-pyridin-4-ylamino)-ethanol

(S)-1-(3-Chloro-phenyl)-2-(3-[1,3]dioxolan-2-yl-2-methoxy-pyridin-4-ylamino)-ethanol:A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g,10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol),CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K₃PO₄ (6.3g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for22 h (CuI and K₃PO₄ were crushed into powders before added). Aftercooled down to room temperature, the reaction mixture was loaded onsilica gel. The chromatography with eluant CH₂Cl₂: MeOH=100:1 affordedthe title product (1.27 g, 38%). ¹H NMR (CDCl₃) δ 3.30 (m, 1H) 3.45 (m,1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H),6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H).ESI-MS m/z 351.4 (MH⁺).

4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde

4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde:To a mixture of(S)-1-(3-chloro-phenyl)-2-(3-[1,3]dioxolan-2-yl-2-methoxy-pyridin-4-ylamino)-ethanol(223 mg, 0.64 mmol) and H₂O (0.75 mL) was added HCl solution in dioxane(4 M, 10 mL). After it was heated at 70° C. for 4 h, the reactionmixture was evaporated to dryness. HPLC purification of the residueafforded the title compound (20.1 mg, 11%). ¹H NMR (DMSO-d₆) δ 3.37 (m,1H) 3.58 (m, 1H), 4.58 (m, 1H), 5.95 (d, J=6 Hz, 1H), 7.30-7.40 (3H),7.49 (s, 1H), 9.94 (s, 1H, CHO), 10.30 (m, 1H, NH), 10.95 (m, 1H, 1H).ESI-MS m/z 293.3 (MH⁺).

6.2. Example 2 Kinase Assays

The IGF1R tyrosine kinase is assayed in Kinase-Glo ATP depletion assayusing the synthetic polymer poly(Glu-Tyr, 4:1) (Sigma Chemicals) as aphosphoacceptor substrate. Each reaction mixture consists of a totalvolume of 10 μl and contains 40 ng of the enzyme, 5 μg of poly(Glu-Tyr),10 μM of ATP and variable concentrations of test compounds. The mixturesalso contain 50 mM Tris-HCl, pH 7.5; 5 mM MgCl₂; 5 mM MnCl₂; 2 mM DTTand 0.01% Tween 20. The reaction mixtures are incubated at 37° C. for 60minutes and residual concentration of ATP in the mixture is determinedby adding luciferase-containing Kinase-Glo (Promega) development reagentand counting luminescence levels using Fusion Universal MicroplateAnalyzer (PerkinElmer). Tested compounds are dissolved in dimethylsulfoxide to a stock concentration of 10 mM and are typically evaluatedin the assay at eight concentrations in 1 nM to 20 μM range, each inquadruplicate. The final concentration of DMSO added to the kinaseassays is 0.5% or less, which has been shown to have no effect on kinaseactivity. IC₅₀ values are derived by non-linear regression analysisusing Prism 3.0 software (Graphpad Software). Other tyrosine kinases areassayed according to the same protocol after titrating amount of theenzyme to provide optimal signal-to-noise ratio and no more than 30% oftotal ATP consumption in the reaction conditions used.

The IGF1R tyrosine kinase is assayed in Phosphotyrosine (PT66 or PT 100)AlphaScreen chemiluminescent assay (PerkinElmer) according to themanufacturerer's recommendations. Each kinase reaction mixture consistsof a total volume of 15 μl and contains 0.1-1 ng of the enzyme, 7 ng ofbiotinylated poly(Glu-Tyr) (Cis-Bio), 10 μM of ATP and variableconcentrations of test compounds. The mixtures also contain 50 mMTris-HCl, pH 7.5; 5 mM MgCl₂; 5 mM MnCl₂; 2 mM DTT and 0.01% Tween 20.The reaction mixtures are incubated at room temperature for 30 minutes.Ten (10) μl of the mixture of receptor and donor beads (as supplied bythe manufacturer) is then added to the reaction and the incubation iscontinued for an additional 60 minutes. The reaction is stopped byaddition of 10 μl of detection Buffer (62.5 mM HEPES, pH 7.4; 250 mMNaCl, 100 mM EDTA, 0.25% BSA. Data are collected as optical readings at520-620 nm on an AlphaScreen Fusion microplate reader (PerkinElmer) andthe IC50 values are calculated using the software Prism 3.0, a graphingprogram from GraphPad Software. Other tyrosine kinases are assayedaccording to the same protocol after titrating amount of the enzyme toprovide optimal signal-to-noise ratio. Table III below shows exemplarydata for biochemical inhibition (IC50).

6.3. Example 3 ELISA-Based Assay of IGF1 Receptor AutophosphorylationInhibition in Cells

MCF7 human breast cancer cells expressing IGF1 receptor or an engineeredhuman fibroblast cell line NIH 3T3 overexpressing full-length IGF1R arean exemplary cellular models in which to perform such assays. Such cellsmay be maintained in DMEM medium supplemented with 10% fetal bovineserum (FBS), 4% L-glutamine, 1% antibiotic solution(penicillin-Streptomycin) in a humidified atmosphere of 95% air and 5%CO₂ at 37° C. Confluent cells in T175 cell culture flasks are incubatedovernight with serum-free DMEM medium. After the serum starvation step,the cells are detached and split into a standard 96-well cell cultureplate (one T175 flask per plate, 30 μl of cell suspension per platewell). Tested inhibitors from their 10 mM stock solutions in DMSO aresubsequently added at various concentrations in serum-free DMEM mediumfor 1 hour incubation at 37° C. in CO₂-incubator; total DMSOconcentration in both treated and control wells is adjusted to 1%. Cellsare then stimulated for 10 minutes with 100 nM IGF-1 added in 30 μlDMEM. After treatment, cells are lysed by addition of 30 μl of 4× lysisbuffer (phosphate-buffered saline (PBS), 2% Triton-X100, 1 mMphenylmethylsulphonyl fluoride (PMSF) and 8 mM activated orthovanadate),mixing and incubation for 15 minute at room temperature. To prepareassay plates, 96-well ELISA Plates (Pierce Chemical, Reacti-bind plates)were coated by goat-anti-rabbit Fc antiserum by adding 0.25 μg antiserumper well in 0.2M sodium bicarbonate buffer per well and incubatingovernight at 4° C. After incubation, the plate is washed three times byPBS with 0.02% Tween-20, supplied with 25 ng/50 μl per well ofanti-IGF1R antibody (C-20, Santa Cruz Biotechnology) and incubated forseveral hours to overnight. Prior to the addition of the preparedcellular lysates, the antibody solution is aspirated, wells washed withPBS and supplied with 25 μl per well of Starting Block buffer (PierceChemical).

To measure tyrosine phosphorylation of the beta-subunits of the IGF1R,25-50 μl of the lysates are transferred from the stimulation plate tothe wells of the prepared assay plate and incubated overnight at 4° C.The wells are washed with PBS with 0.02% Tween-20, incubated with 50 μlof 1:3000 dilution of anti-phosphotyrosine 4G10-HRP antibody conjugate(Upstate Biotechnology) for 2 hours at room temperature and washedagain. The assay plate was developed with Ultra TMB ELISA HRP substrate(Pierce Chemical) and absorbance of the wells was read at 450 nm inELISA plate reader. Alternatively, 10-50 times larger volumes of lysatesprepared as described above are incubated overnight at 4° C. with 1 μgof anti-IGF1R antibody (C-20; Santa Cruz Biotechnology) and 20 μl of 50%protein-A agarose slurry. After 3 washes with lysis buffer, pellets areresuspended in SDS-PAGE sample buffer and boiled for 3 minutes. Proteinsare resolved by SDS-PAGE (7.5%) and transferred by electroblotting ontonitrocellulose membranes. Tyrosine phosphorylated IGF1R is detected byimmunoblotting with anti-phosphotyrosine antibody (4G10, UpstateBiotechnology) and, in a separate identical blot, with anti-IGF1Rantibody. Table III below shows exemplary data for cellular receptorphosphorylation inhibition in terms of IC50 value.

6.4. Example 4 Cell Proliferation Inhibition Assay

IGF1R and other tyrosine kinase inhibitors can inhibit the proliferationof certain cancer cell lines indicating their possible therapeuticutility for treating the corresponding cancer types. Cancer cell linesof interest and control normal lines, including CHO, HEK293, BA/F3,COL0205, PC3, DU145, MCF₇, Panc1, ACHN, Hep G2, H460, K₅₆₂, TT, U87-MG,CAOV-3, SK-MEL5, Karpas 299 and human multiple myeloma cell lines H929,MM1s, MM1r, UTMC2, CPM2, KMS11, My5, KMS12PE, My7, JJN3, KMS18, U266,SKMM2, RPMI-8226 are plated in white, clear-bottomed 384-well cellculture plates at 2500-5000 cells per well and supplied with dilutionsof tested compounds After a desired period of time (typically 3 days),the number of viable cells is quantitated by using Cell Titer-GloLuminescent Cell Viability Assay (Promega), a cell proliferation assaysystem based on detection of total amount of ATP present as a measure ofcell metabolic activity. The plated cells are mixed with the CellTiter-Glo developing reagent and counted in a luminescence multiwellplate reader according to the standard manufacturer's protocol togenerate IC50 curves for cell proliferation inhibition. Results aretypically reported as percent of growth (% viability═(OD_(72h(compound))−OD_(day0)))/(OD_(72h(no compound))−OD_(day0)).Alternatively, viable cells are quantitated by using the conventionalcolorimetric MTT assay. The MTT assay is based on the cleavage of theyellow tetrazolium salt MTT to purple formazan crystal by metabolicactive cells. The formazan is then solubilized, and the concentrationdetermined by optical density at 570 nm. The cells plated and incubatedwith a compound as described above are supplemented with the solution ofMTT and incubated for 2-3 hours. The growth medium is removed anddimethyl sulfoxide is added into each well to dissolve the formazan. Theabsorbance is measured on an ELISA plate reader with a test wavelengthof 570 nm and a background subtraction wavelength of 630 nm to obtainsample signal (OD570-OD630). Table III below shows the results of cellproliferation inhibition assay for some exemplary compounds of thisinvention for the following cell lines—MM Is (multiple myeloma), H929(multiple myeloma), COL0205 (colon carcinoma), HEK293 (human normalembryonic kidney), CHO (chinese hamster ovary). The results are reportedin terms of IC50 value for a particular compound and a cell line in thestandard 3-day proliferation assay using Cell Titer-Glo. Table IV belowshows the results of cell proliferation assay for some exemplarycompounds of this invention for the following human multiple myelomacell lines —H929, MM1s, MM1r, UTMC2, CPM2, KMS11, My5, KMS12PE, My7,JJN3, KMS18, U266, SKMM2, RPMI-8226 as well as HEK293 (human normalembryonic kidney), CHO (chinese hamster ovary). The results are reportedin terms of IC50 value for a particular compound and a cell line in thestandard 3-day proliferation assay using MTT assay.

TABLE III MCF7 IGF1R Phos- Karpas- HEK phoryl- ALK InsR IGF1R JAK2 TrkABa/F3 299 K562 293 CHO H929 ation # Structure IC50 IC50 IC50 IC50 IC50IC50 IC50 IC50 IC50 IC50 IC50 IC50 1

++ +++ +++ ++ + + ++ +++ 2

− − − − − + + − 3

+ ++ ++ − − + + + 4

++ ++ ++ ++ + ++ + + 5

+++ ++ ++ ++ ++ ++ ++ 6

++ ++ +++ ++ + ++ 7

− + ++ ++ 8

++ ++ ++ ++ − − − 9

++ ++ ++ ++ 10

− ++ + + − 11

+ + − + ++ 12

− − − − ++ 13

++ +++ +++ ++ ++ 14

− ++ ++ ++ ++ 15

+ +++ +++ ++ +++ ++ + ++ ++ 16

+++ +++ +++ ++ +++ − + + 17

− 18

++ ++ +++ ++ − 19

++ ++ +++ ++ − 20

++ ++ ++ ++ − 21

++ ++ ++ ++ + 22

++ ++ ++ ++ − 23

+ ++ ++ ++ + 24

++ +++ +++ ++ 25

+ +++ +++ +++ 26

− + ++ ++ + + 27

− − − − 28

+ + − + − − − − 29

− − − − + + ++ − 30

− − − − − − − − 31

− ++ + + − − + + ++ + 32

− − + − ++ − − + + 33

++ +++ +++ ++ − − ++ − 34

++ ++ +++ ++ − − − + − 35

++ +++ +++ ++ − − − + 36

− − − − − − − ++ 37

+ +++ − ++ − − − ++ + 38

++ ++ ++ ++ − − + ++ 39

++ ++ ++ ++ ++ ++ ++ 40

+ + + ++ ++ + + 41

+ ++ ++ + ++ ++ + + 42

+ ++ +++ + − − + + 43

− ++ ++ ++ − + + 44

− ++ ++ ++ − + + 45

++ ++ ++ ++ + + 46

− ++ +++ − + + 47

+ ++ ++ ++ + + 48

+ +++ +++ ++ ++ ++ 49

++ ++ ++ ++ − − − 50

+ + ++ ++ − − − 51

− − − − − − − 52

++ ++ +++ ++ − − − 53

++ + + ++ − − − 54

+ ++ +++ − + + + 55

++ ++ +++ ++ ++ ++ ++ 56

++ ++ ++ ++ ++ ++ ++ 57

++ ++ ++ ++ ++ + + 58

++ ++ ++ + + + + 59

++ +++ +++ ++ ++ ++ + + ++ ++ 60

+ ++ ++ ++ − − − 61

− + ++ + − − − 62

+ ++ +++ + + + ++ 63

++ − − − − − − 64

+ ++ +++ ++ + − + − 65

− + + + − − − 66

− − − − − − − 67

+ + − ++ − − − 68

+ ++ +++ ++ − − − 69

+ ++ ++ ++ − − − 70

+ + + ++ − − − 71

+ ++ ++ + − − − 72

++ ++ ++ ++ − − − 73

+ ++ ++ ++ − ++ ++ 74

+ ++ ++ ++ ++ ++ ++ 75

++ ++ ++ ++ ++ ++ ++ 76

++ ++ ++ ++ ++ ++ ++ 77

++ + ++ ++ − − − 78

++ ++ +++ ++ − + + 79

++ ++ ++ ++ + + ++ 80

++ + ++ + − + + 81

++ + ++ + + + − 82

++ ++ +++ ++ − − − 83

++ +++ +++ ++ − − − 84

++ ++ ++ ++ − − − ++ ++ 85

++ +++ +++ ++ ++ ++ ++ 86

++ + ++ ++ − + + − 87

++ +++ +++ ++ − + + + ++ 88

++ ++ ++ ++ + + + + ++ 89

++ ++ ++ ++ + ++ + + ++ 90

− + + ++ + ++ ++ + 91

++ ++ + ++ − + − ++ ++ 92

− + + + − − − ++ 93

− +++ +++ − − + − + ++ ++ 94

++ +++ +++ ++ − − − − + ++ 95

++ +++ +++ ++ − + + + + + 96

− +++ ++ + − − − + + 97

+ ++ ++ ++ − − − − + ++ 98

++ +++ +++ + − − − + + 99

+ ++ +++ ++ − − − − 100

+++ ++ ++ ++ − + + 101

+++ +++ +++ ++ − − − 102

− + +++ − − + − 103

− + +++ + ++ ++ ++ 104

+ +++ ++ + − − − 105

+ ++ ++ ++ − − + 106

++ +++ +++ ++ + − + + + 107

++ +++ +++ ++ − − − + + 108

++ ++ ++ ++ − + + + 109

− − − − − ++ 110

++ +++ +++ ++ + ++ + + + 111

++ ++ ++ ++ + ++ − − 112

++ ++ ++ ++ + ++ + 113

+++ ++ ++ ++ − − − − 114

++ +++ +++ ++ − − − − 115

++ +++ +++ ++ − + 116

+ +++ +++ ++ − + − − 117

+ +++ +++ ++ − + − − 118

++ +++ +++ ++ − + − − 119

++ +++ +++ ++ − − − 120

++ +++ +++ ++ ++ ++ 121

++ ++ ++ ++ ++ + 122

+ ++ +++ ++ − − 123

++ ++ +++ ++ − − − − 124

++ ++ ++ ++ − + − − 125

++ ++ +++ ++ − − − − 126

+ ++ +++ ++ ++ ++ + + 127

++ ++ +++ ++ − − − − 128

++ ++ +++ ++ − − − 129

++ +++ +++ ++ + + + + 130

++ +++ +++ +++ − − − ++ ++ 131

+ ++ + ++ +++ − − + ++ + ++ ++ 132

++ +++ +++ +++ − − − +++ ++ 133

++ +++ +++ +++ +++ 134

+ +++ +++ +++ +++ 135

++ ++ +++ ++ +++ − − − − 136

++ ++ +++ ++ − − − − 137

+ +++ ++ ++ − − − − 138

++ +++ +++ ++ + ++ − 139

++ +++ +++ ++ − − − ++ ++ 140

++ +++ +++ +++ + + − +++ ++ 141

++ +++ +++ +++ − − − +++ ++ 142

++ +++ +++ ++ + + + +++ 143

+++ ++ +++ ++ − − + +++ 144

+++ ++ +++ +++ − + + ++ ++ 145

− +++ +++ ++ − − + + + ++ ++ 146

++ +++ +++ +++ − − + 147

+ +++ +++ +++ − − ++ 148

++ +++ +++ +++ − + + 149

+++ +++ +++ +++ + − ++ 150

++ +++ +++ +++ − + 151

+ +++ +++ +++ − + 152

++ +++ +++ +++ − + 153

+ +++ +++ +++ − + 154

− +++ +++ +++ − + 155

+ +++ +++ +++ − + 156

++ +++ +++ +++ − + 157

++ +++ +++ +++ − − 158

+ +++ +++ +++ − + 159

+ +++ +++ +++ − + 160

++ +++ ++ ++ − + 161

++ +++ +++ ++ − + − − − + 162

++ +++ +++ +++ + + + 163

++ +++ +++ +++ + − + 164

++ +++ +++ +++ + + + 165

++ +++ +++ +++ − + ++ 166

++ +++ +++ +++ − + ++ 167

++ +++ +++ +++ − − ++ 168

++ +++ +++ +++ − − + 169

++ +++ +++ +++ − − − 170

+ ++ + ++ The IC50 values are represented as ranges where IC50 values inthe range below 0.5 μM are indicated by “+++”, between 0.5 μM and 5 μMby “++”, between 5 μM and 15 μM by “+” and above 15 μM by “−”.Biochemical assays are designated by the name of the tyrosine kinase andthe cell proliferation assays by the name of the corresponding cellline; IC50 data for IGF1R phosphorylation inhibition in MCF7 cells asmeasured by ELISA assay is also included.

TABLE IV HEK CHO H929 MM1S MM1R UTMC2 CPM2 KMS11 Structure IC50 IC50IC50 IC50 IC50 IC50 IC50 IC50

E E A A B B C C

E E B B C A C C

E E B C C B D D

E E A A B A C C

E E B A C A C C

E E B B C A C C

E E C C C A C D KMS- RPMI- My5 12PE My7 JJN3 KMS18 U266 SKMM2 8226Structure IC50 IC50 IC50 IC50 IC50 IC50 IC50 IC50

C C C C C C D D

D C C C D C C D

D D D D D D D D

C C C C B C C D

D D C C C C D D

D C D C C C D D

D D D D D C D D The IC50 values of multiple myeloma cell lineproliferation inhibition are represented as ranges where IC50 values inthe range below 0.5 μM are indicated by “A”, between 0.5 μM and 1 μM by“B”, between 1 μM and 5 μM by “C”, between 5 μM and 20 μM by “D”, and ator above 20 μM by “E”.

6.5. Example 5 Kinase Profiling

Table V shows the results of kinase inhibition profiling of one of thecompounds provided herein. The results are reported in terms of degreeof inhibition for a particular kinase at fixed concentration of thecompound (2 μM) being tested where “−” indicates less than 10%inhibition, “+”—more than 10% but less than 30%, “++”—more than 40% butless than 75% and “+++”—more than 75% inhibition of the target proteinkinase compared to the activity of the kinase in a control to which notest compound has been added. Kinase profiling technique which has beenused to evaluate compounds is described above and further technicaldetails can be found at Upstate Biotechnologies Web site(http://www.upstatebiotech.com).

TABLE V Kinase Percent Inhibition KIT +++ FGFR1 +++ FLT1 +++ IGF1R +++IR +++ MET − PDGFRb + TRKA +++ Abl ++ Src +++ ErbB4 + Flt3 +++ Flt4 +++KDR ++ PDK1 − PKBa − MAPK1 − PKA − CDK1/Cyclin B − cRaf −

All publications, patents and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

1. A compound according to formula 1, or a stereoisomer, tautomer, salt,hydrate or prodrug thereof:

wherein: each W¹ through W⁶ is independently a carbon atom or a nitrogenatom with the proviso that when any W¹ through W⁶ is N, then thecorresponding substituent(s) X¹ through X⁶ is (are) absent; each X¹through X³ and X⁵ and X⁶ is independently selected from hydrogen,hydroxy, halogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, optionally substituted acylamino, optionallysubstituted sulfonamido, optionally substituted ureido, trifluoromethyl,trifluoromethoxy, nitro, cyano, optionally substituted aryl orheteroaryl, aryloxy or heteroaryloxy, arylamino or heteroarylamino(substituted by one or more groups selected from lower alkyl, loweralkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,carboxamide, sulfonamide, sulfamide, ureido, methylenedioxy,ethylenedioxy, primary, secondary or tertiary amino, mono or dialkylamido, heterocyclylamido, optionally substituted heterocyclyl orcycloalkyl, optionally substituted heterocyclylalkyl, heteroalkyl),nitrogen-heterocyclyl, connected either by its nitrogen, or a carbonatom (such as piperazino, homopiperazino, morpholino, thiomorpholino,thiomorpholino-5-oxide, thiomorpholino-S,S-dioxide, pyrrolidino,piperidino, azetidino), nitrogen-heterocyclyl-alkyl, connected either byits nitrogen or a carbon atom (such as piperazinomethyl,piperazinoethyl, homopiperazinomethyl, morpholinomethyl,thiomorpholinomethyl, thiomorpholino-5-oxide-methyl,thiomorpholino-S,S-dioxide-methyl, pyrrolidinomethyl, piperidinoethyl,azetidinomethyl, all optionally substituted by groups selected fromhydroxyalkyl, lower alkoxyalkyl, primary, secondary, or tertiaryamino-alkyl, lower alkyl cycloalkyl or heterocycloalkyl); wherein aryland heteroaryl groups can be bicyclic; and wherein any adjacent pair ofX¹ through X³ can be joined to form a cycloalkyl, cycloheteroalkyl, arylor heteroaryl ring fused to the ring comprising W¹ through W³, wherein afused ring is naphthyl, benzodioxolyl, benzofuranyl, benzodioxinyl,dihydrobenzodioxinyl or quinolinyl; X⁴ is selected from hydrogen,hydroxy, halogen, trifluoromethyl, trifluoromethoxy, optionallysubstituted (alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl,heterocycloalkyl), optionally substituted (aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroaryalkoxy,arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl,heteroarylsulfonyl, arylsulfonamido, heteroarylsulfonamido,arylaminosulfonyl, heteroarylaminosulfonyl), by substituents selectedfrom halogen, hydroxy, amino, cyano, nitro, carboxamido, sulfonamido,alkoxy, amino, lower-alkylamino, di-lower-alkylamino, cycloalkyl,cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy, trifluoromethyl,trifluoromethoxy, methylenedioxy, ethylenedioxy, methanesulfonyl,trifluoromethanesulfonyl, dialkylaminoalkyl, dialkylaminoalkoxy,heterocyclyl, heteroalkyl and heterocyclylalkyl; or is selected from thefollowing groups:

 wherein: m is an integer from 1 to 4, and n is an integer from 0 to 4;R² is selected from optionally substituted aryl, or heteroaryl,—(CH₂)_(o)-aryl, —(CH₂)_(o)-heteroaryl, —(CH₂)_(p)-M¹-aryl,—(CH₂)_(p)-M¹-heteroaryl substituted by a substituent independentlyselected from a group consisting of hydrogen, hydroxy, halogen,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethanesulfonyl, 2,2,2-trifluoroethoxy, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, methylenedioxy, ethylenedioxy,trimethylene, dimethyleneoxy, cyano, nitro, primary, secondary ortertiary amino, such as dimethylamino, carboxamide, sulfonamide, loweralkylsulfonyl, lower alkylsulfinyl, lower alkylthio, loweralkylthioalkyl, lower alkylsulfonylalkyl, optionally substituted aryl orheteroaryl., wherein M¹ is a —(CH₂)— or a heteroatom O, S, or N—R*; R³is selected from optionally substituted aryl, heteroaryl,—(CH₂)_(o)-aryl, —(CH₂)_(o)-heteroaryl, —(CH₂)_(p)-M²-aryl,—(CH₂)_(p)-M²-heteroaryl, substituted by a substituent independentlyselected from a group consisting of hydrogen, hydroxy, halogen,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethanesulfonyl, 2,2,2-trifluoroethoxy, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, methylenedioxy, ethylenedioxy,trimethylene, dimethyleneoxy, cyano, nitro, primary, secondary ortertiary amino, such as dimethylamino, carboxamide, sulfonamide, loweralkylsulfonyl, lower alkylsulfinyl, lower alkylthio, loweralkylthioalkyl, lower alkylsulfonylalkyl, optionally substituted aryl orheteroaryl, wherein M² is a heteroatom O, S, or N—R**); R** is selectedfrom hydrogen, hydroxy, lower alkyl, lower alkoxy, acyl, optionallysubstituted aryl, heteroaryl, alkylsulfonyl or arylsulfonyl; and each(CH₂)_(m) or (CH₂)_(n) can be optionally substituted with one or moregroups selected from hydrogen, halogen, hydroxy, carboxamido, loweralkylcarbonyl, hydroxy-lower alkyl, hydroxycycloalkyl, optionallysubstituted (primary, secondary or tertiary amino, lower alkoxy, loweralkyl, lower heteroalkyl, cycloalkyl, heterocyclo, heterocycloalkyl,aryl, heteroaryl, aryloxy or heteroaryloxy), by groups selected fromhalogen, hydroxy, amino, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, trifluoromethanesulfonyl, cyano,nitro, carboxamido, lower alkylthio, lower alkylsulfoxy, loweralkylsulfonyl, arylthio, arylsulfoxy, arylsulfonyl, lower alkylcarbonyl,arylcarbonyl) all groups optionally substituted by groups selected fromhydrogen, halogen, lower alkyl, trifluoromethyl, trifluoromethoxy, loweralkoxy, lower alkylthio, hydroxy, sulfonamido, and lower acylamino; or(CH₂)_(m) and (CH₂)_(n) can form a cyclic structure and one or moremethylene of (CH₂)_(m) or (CH₂)_(n) can be replaced by a heteroatomselected from O, N and S; Y¹ is independently selected from:

 wherein: q is an integer from 0 to 4; R#₁₀ is selected from hydrogen,lower alkyl, hydroxy and lower alkoxy; each (CH₂)_(q) can be optionallysubstituted with one or more groups selected from hydrogen, lower alkyl,heteroalkyl, heterocyclo, hydroxy-lower alkyl, cycloalkyl andhydroxycycloalkyl, wherein such substituents can be joined to form acyclic structure and wherein one or more of the methylene groups of(CH₂)_(q) can be replaced by a carbonyl group (C═O); Y² is independentlyselected from:

 wherein: r is an integer from 0 to 4; R#₁₁ is selected from hydrogen,lower alkyl, hydroxy and lower alkoxy; each (CH₂)_(r) can be optionallysubstituted with one or more groups selected from hydrogen, lower alkyl,heteroalkyl, heterocyclo, hydroxy-lower alkyl, cycloalkyl,hydroxycycloalkyl, wherein such substituents can be joined to form acyclic structure, and wherein one or more of the methylene groups of(CH₂)_(r) can be replaced by a carbonyl group (C═O); and R¹ isindependently selected from optionally substituted heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocyclyloxyalkyl,heteroalkyl, heterocyclylaminoalkyl, aminoalkyl, lower alkylaminoalkyl,di-(lower alkyl)-aminoalkyl, aminocycloalkyl, alkylaminocycloalkyl,di-(lower alkyl)-aminocycloalkyl, di-(lower alkyl)-aminocycloalkylalkyl,by groups selected from hydrogen, lower alkyl, hydroxy, lower alkoxy,amino, amidino, carboxamido, sulfonamido, hydroxy, cyano, primary,secondary or tertiary amino, halo, azido, lower alkoxyalkyl, cyanoalkyl,azidoalkyl, haloalkyl, hydroxyalkyl, methanesulfonylalkyl, primary,secondary or tertiary amino-alkyl, optionally substituted aryl,heteroaryl, heteroalkyl, heterocyclyl, cycloalkyl, alkenyl and alkynyl.2. The compound according to claim 1, wherein X⁴ is selected from:

wherein: L is selected from O, S, N—R#₉; R#₉ is selected from hydrogen,lower alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl,optionally substituted aryl, heteroaryl, arylalkyl, heteroarylalkyl bygroups selected from hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, trifluoromethoxy, lower alkylthio, nitro, azido, cyano,amido and ureido; and each X* is independently selected from hydrogen,lower alkyl, halogen, lower alkoxy, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, azido, cyano, nitro, methylenedioxy, trimethyleneand dimethyleneoxy.
 3. The compound according to claim 1, wherein X⁴ isselected from

wherein: X*A is hydrogen, halogen, optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio,cycloalkylthio, alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano; X*B is hydrogen, halogen, optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio,cycloalkylthio, alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano; X*C is hydrogen, halogen, optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio,cycloalkylthio, alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano; X*D is hydrogen, halogen, optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio,cycloalkylthio, alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano; X*E is hydrogen, halogen, optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio,cycloalkylthio, alkylsulfonyl, cycloalkylsulfonyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, arylthio, arylsulfonyl, heteroarylthio,heteroarylsulfonyl; trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, heteroalkyl, dialkylamino, momoalkylamino, amino,nitro, cyano; X*B and X*C or independently X*C and X*D or independentlyX*D and X*E are taken together to form a 5-7 membered heterocyclic ring,optionally substituted with a lower alkyl or halogen; and X*B and X*C orindependently X*C and X*D or independently X*D and X*E are takentogether to form a condensed aromatic or heteroaromatic ring optionallysubstituted with lower alkyl, lower alkoxy, halogen, trifluoromethyl,cyano, or nitro.
 4. The compound according to claim 1, wherein R¹ isselected from the group consisting of:

wherein: R¹³ is selected from hydrogen, lower alkyl, heteroalkyl,heterocyclyl, cycloalkyl and heterocycloalkyl; R¹⁴ is selected fromhydrogen, hydroxy, lower alkoxy, di-(lower alkyl)amino, lower alkyl,heteroalkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, loweralkoxyalkyl, cyanoalkyl, azidoalkyl, nitroalkyl, ketoalkyl,methanesulfonylalkyl, aminoalkyl, lower alkylaminoalkyl, di-(loweralkyl)aminoalkyl, optionally substituted aryl, heteroaryl, arylalkyl,heteroarylalkyl; R¹⁵ is selected from hydrogen, amino, lower alkylamino,di-(lower alkyl)amino, hydroxy, lower alkoxy, heteroalkyl, loweralkoxyalkyl, aminoalkyl, lower alkylaminoalkyl and di-(loweralkyl)aminoalkyl; a is an integer from 0 to 4; and t, u, v areindependent integers from 0 to
 5. 5. The compound according to claim 1,wherein R¹ is selected from:


6. The compound according to claim 1, wherein the methylene chainbetween the connection and the heteroatom in R¹ may be optionallysubstituted by one or more hydrogen, lower alkyl, hydroxy, hydroxy-loweralkyl, lower alkoxy, carboxamido or sulfonamido; and one of themethylene groups can be substituted by a heteroatom, such as O,NR*** orS, S═O, or S(═O)₂, wherein R*** is selected from hydrogen, hydroxy,lower alkyl, lower alkoxy, heteroalkyl, hydroxyalkyl, aminoalkyl, loweralkylaminoalkyl and di-(lower alkyl)aminoalkyl.
 7. The compoundaccording to claim 1 having the following formula (1a):

wherein W¹ is nitrogen or carbon.
 8. The compound according to claim 1having the following formula (1b):


9. The compound according to claim 1 having the following formula (1c):


10. The compound according to claim 1 having the following formula (1d):


11. (canceled)
 12. The compound according to claim 1 having thefollowing formula (1f):


13. (canceled)
 14. The compound according to claim 1 having thefollowing formula (1h):


15. (canceled)
 16. The compound according to claim 1 having thefollowing formula (1j):


17. (canceled)
 18. The compound according to claim 1 having thefollowing formula (1l):

wherein X²⁰ to X²⁴ are each independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy.
 19. Thecompound according to claim 1 having the following formula (1m):

wherein X²⁰ to X²⁴ are each independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy.
 20. Thecompound according to claim 1 having the following formula (1n):

wherein X²⁰ to X²⁴ are each independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy.
 21. Thecompound according to claim 1 having the following formula (1o):

wherein X²⁰ to X²⁴ are each independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy.
 22. Thecompound according to claim 1 having the following formula (1p):

wherein X³⁰ to X³⁴ are independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy.
 23. Thecompound according to claim 1 having the following formula (1q):

wherein X³⁰ to X³⁴ are independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy. 24.(canceled)
 25. The compound according to claim 1 having the followingformula (1s):

wherein X³⁰ to X³⁴ are independently selected from hydrogen, loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, cyano, nitro, ureido, primary, secondary or tertiaryamino, methylenedioxy, ethylenedioxy and difluoromethylenedioxy. 26-29.(canceled)
 30. The compound according to claim 1, wherein the compoundis:(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-(pyrrolidin-1-yl)propyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;(R)-2-(4-(3-(2-bromophenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;(R)-2-(4-(3-(6-ethylbenzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;(R)-2-(4-(3-(2-chloro-4-methoxyphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one;or(R)-2-(4-(3-(2,4-dimethylphenoxy)-2-hydroxypropylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-(3-oxobutyl)piperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one.31. A pharmaceutical composition comprising a compound according toclaim 1 and one or more pharmaceutically acceptable diluents, excipientsor carriers. 32-34. (canceled)
 35. A method of treating or preventing acondition or disorder related to tyrosine kinase activity comprisingadministering a compound according to claim 1, wherein said condition ordisorder is selected from the group consisting of cancer diabetes,restenosis arteriosclerosis, psoriasis, angiogenic diseases andimmunologic disorder.
 36. (canceled)
 37. A method of inhibiting atyrosine kinase activity comprising contacting the tyrosine kinase witha compound according to claim
 1. 38. The method of claim 37, whereinsaid tyrosine kinase is selected from the group consisting of Alk, Axl,CSFR, DDR1, DDR2, EphB4, EphA2, EGFR, Flt-1, Flt3, Flt4, FGFR1, FGFR2,FGFR3, FGFR4, HER2, HER3, HER4, IR, IGF1R, IRR, Kit, KDR/Flk-1, Met,Mer, PDGFR.alpha., PDGFR.beta., Ret, Ros, Ron, Tie1, Tie2, TrkA, TrkB,TrkC, Abl, Arg, Ack, Blk, Bmx, Brk, Btk, Csk, Fak, Fes, Fgr, Fps, Frk,Fyn, Hck, Itk, Jak1, Jak2, Jak3, Lck, Lyn, Src, Syk, Tec, Yes and ZAP70.